Publications by authors named "Rama Suresh"

36 Publications

Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets.

RSC Med Chem 2021 Nov 13;12(11):1808-1825. Epub 2021 Jul 13.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health Bethesda MD 20892-0810 USA +301 480 8422 +301 496 9024.

Nucleoside derivatives are well represented as pharmaceuticals due to their druglike physicochemical properties, and some nucleoside drugs are designed to act on receptors. The purinergic signaling pathways for extracellular nucleosides and nucleotides, consisting of adenosine receptors, P2Y/P2X receptors for nucleotides, and enzymes such as adenosine (ribo)kinase, have been extensively studied. A general modification, a constrained, bicyclic ring system (bicyclo[3.1.0]hexane, also called methanocarba) substituted in place of a furanose ring, can increase nucleoside/nucleotide potency and/or selectivity at purinergic and antiviral targets and in interactions at diverse and unconventional targets. Compared to other common drug discovery scaffolds containing planar rings, methanocarba nucleosides display greater sp3 character ( more favorable as drug-like molecules) and can manifest as sterically-constrained North (N) or South (S) conformations. Initially weak, off-target interactions of (N)-methanocarba adenosine derivatives were detected as leads that were structurally optimized to enhance activity and selectivity toward target proteins that normally do not recognize nucleosides. By this approach, novel modulators for 5HT serotonin and κ-opioid receptors, dopamine (DAT) and ATP-binding cassette (ABC) transporters were found, and previously undetected antiviral activities were revealed. Thus, through methanocarba nucleoside synthesis, structure-activity relationships, and multi-target pharmacology, a robust purinergic receptor scaffold has been repurposed to satisfy the pharmacophoric requirements of various GPCRs, enzymes and transporters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1md00167aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597424PMC
November 2021

Pharmacological characterization of DPTN and other selective A adenosine receptor antagonists.

Purinergic Signal 2021 Oct 28. Epub 2021 Oct 28.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0810, USA.

The A adenosine receptor (AR) is emerging as an attractive drug target. Antagonists are proposed for the potential treatment of glaucoma and asthma. However, currently available AAR antagonists are potent in human and some large animals, but weak or inactive in mouse and rat. In this study, we re-synthesized a previously reported AAR antagonist, DPTN, and evaluated its affinity and selectivity at human, mouse, and rat ARs. We showed that DPTN, indeed, is a potent AAR antagonist for all three species tested, albeit a little less selective for mouse and rat AAR in comparison to the human AAR. DPTN's K values at respective A, A, A, and A receptors were (nM) 162, 121, 230, and 1.65 (human); 411, 830, 189, and 9.61 (mouse); and 333, 1147, 163, and 8.53 (rat). Its antagonist activity at both human and mouse AARs was confirmed in a cyclic AMP functional assay. Considering controversial use of currently commercially available AAR antagonists in rats and mice, we also re-examined other commonly used and selective AAR antagonists under the same experimental conditions. The K values of MRS1523 were shown to be 43.9, 349, and 216 nM at human, mouse, and rat AARs, respectively. MRS1191 and MRS1334 showed incomplete inhibition of [I]I-AB-MECA binding to mouse and rat AARs, while potent human AAR antagonists, MRS1220, MRE3008F20, PSB10, PSB-11, and VUF5574 were largely inactive. Thus, we demonstrated that DPTN and MRS1523 are among the only validated AAR antagonists that can be possibly used (at an appropriate concentration) in mouse or rat to confirm an AAR-related mechanism or function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11302-021-09823-5DOI Listing
October 2021

Clinical Complete Response in Patients With Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Nonoperative Management.

Int J Radiat Oncol Biol Phys 2021 Oct 12. Epub 2021 Oct 12.

Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri. Electronic address:

Purpose: This study aimed to determine the clinical efficacy and safety of nonoperative management (NOM) for patients with rectal cancer with a clinical complete response (cCR) after short-course radiation therapy and consolidation chemotherapy.

Methods And Materials: Patients with stage I-III rectal adenocarcinoma underwent short-course radiation therapy followed by consolidation chemotherapy between January 2018 and May 2019 (n = 90). Clinical response was assessed by digital rectal examination, pelvic magnetic resonance imaging, and endoscopy. Of the patients with an evaluable initial response, those with a cCR (n = 43) underwent NOM, and those with a non-cCR (n = 43) underwent surgery. The clinical endpoints included local regrowth-free survival, regional control, distant metastasis-free survival, disease-free survival, and overall survival.

Results: Compared with patients with an initial cCR, patients with initial non-cCR had more advanced T and N stage (P = .05), larger primary tumors (P = .002), and more circumferential resection margin involvement on diagnostic magnetic resonance imaging (P < .001). With a median follow-up of 30.1 months, the persistent cCR rate was 79% (30 of 38 patients) in the NOM cohort. The 2-year local regrowth-free survival was 81% (95% confidence interval [CI], 70%-94%) in the initial cCR group, and all patients with local regrowth were successfully salvaged. Compared with those with a non-cCR, patients with a cCR had improved 2-year regional control (98% [95% CI, 93%-100%] vs 85% [95% CI, 74%-97%], P = .02), distant metastasis-free survival (100% [95% CI, 100%-100%] vs 80% [95% CI, 69%-94%], P < .01), disease-free survival (98% [95% CI, 93%-100%] vs 71% [95% CI, 59%-87%], P < .01), and overall survival (100% [95% CI, 100%-100%] vs 88% [95% CI, 79%-98%], P = .02). No late grade 3+ gastrointestinal or genitourinary toxicities were observed in the patients who underwent continued NOM.

Conclusions: Short-course radiation therapy followed by consolidation chemotherapy may be a feasible organ preservation strategy in rectal cancer. Additional prospective studies are necessary to evaluate the safety and efficacy of this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2021.10.004DOI Listing
October 2021

A phase II study of everolimus in patients with advanced solid malignancies with or mutations.

J Thorac Dis 2021 Jul;13(7):4054-4062

Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Background: Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in and , can lead to the dysregulation of this pathway. Furthermore, mutations in and are known to confer sensitivity to everolimus-an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in , or .

Methods: A total of 12 patients with histologically confirmed diagnosis of advanced solid tumors (metastatic, recurrent, or unresectable) with mutations in or genes, who had failed at least one line of standard of care systemic therapy, were enrolled to this open label, single-arm study. Presence of mutations in or genes was assessed using targeted-next generation sequencing (NGS). All eligible patients were treated with everolimus at an initial dose of 10 mg orally once daily in cycles of 28 days. The primary endpoint of this study was overall response rate (ORR).

Results: Of 12 patients enrolled, 8 were evaluable for response at the end of 2 cycles. One complete response (CR) was observed (12.5%) and one patient (12.5%) had stable disease (SD), while six (75%) patients showed disease progression. Everolimus was overall well tolerated with anemia, decreased neutrophil and lymphocyte counts, peripheral edema and hyperglycemia representing the most common adverse events. One patient discontinued treatment due to a treatment related grade 4 pericardial effusion. Both patients with CR or SD had a diagnosis of lung adenocarcinoma with or mutations, respectively.

Conclusions: Although this study failed to meet its prespecified ORR threshold for success of 30% or higher, exploratory analyses suggest potential activity for everolimus in a subset of patients with lung adenocarcinomas with or mutations. Further studies are necessary to systematically explore the clinical activity of everolimus, potentially as a combination therapy, in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd-21-195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339787PMC
July 2021

Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors.

Am J Clin Oncol 2021 09;44(9):443-448

Division of Hematology/Oncology, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC.

Introduction: The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors.

Patients And Methods: Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target.

Results: Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2).

Conclusions: Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/COC.0000000000000852DOI Listing
September 2021

A single-institution phase I feasibility study of dose-escalated IMRT for non-operative locally advanced esophageal carcinoma.

Clin Transl Radiat Oncol 2021 Sep 29;30:19-25. Epub 2021 Jun 29.

Department of Radiation Oncology, Washington University, St. Louis, MO, United States.

Background And Purpose: Radiation dose escalation to improve poor outcomes with chemoradiation in locally advanced esophageal carcinoma is limited in part by increased toxicity. This Phase I study investigates the use of IMRT to improve tolerability of dose escalation.

Materials And Methods: A single-institution, prospective study was conducted between 2007 and 2013 for individuals with inoperable esophageal carcinoma. Gross disease received 60 Gy in 30 fractions and at-risk sites received 54 Gy with simultaneous integrated boost. Concurrent chemotherapy primarily consisted of cisplatin/5-FU. The primary objective was to assess feasibility (<15% rate of grade 4-5 toxicity). Secondary objectives included assessment of overall survival (OS), progression free survival (PFS), and locoregional (LRR) and distant recurrence.

Results: Twenty-six patients were enrolled with median follow up of 17.6 months (range 0.1 to 152.0). The majority were AJCC 7th edition Stage III (54%), distal esophagus primary (81%), and adenocarcinoma histology (85%). Twenty-one patients (81%) completed their course of radiation therapy, while only 55% received 2 cycles of concurrent cisplatin/5-FU. One grade 5 and one grade 4 cardiac event occurred, both during chemoradiation and before receiving 50 Gy. The 3-year OS was 48.6% (95% CI: 32.5 to 72.2%) and PFS was 28.5% (95% CI: 14.6 to 55.5%). Half developed distant failure with LRR occurring in 10 patients (38%), isolated in 5 patients.

Conclusion: While feasibility was demonstrated, toxicity and compliance remained limiting factors with outcomes similar to historical controls. There remains an uncertain role for dose escalation in definitive management of locally advanced esophageal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctro.2021.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267428PMC
September 2021

Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.

Breast Cancer Res Treat 2021 Aug 26;189(1):187-202. Epub 2021 Jun 26.

Lester & Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Purpose: Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR.

Experimental Design: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles.

Results: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR.

Conclusion: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR.

Trial Registration: Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-021-06307-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443324PMC
August 2021

Ligand design by targeting a binding site water.

Chem Sci 2020 Nov 19;12(3):960-968. Epub 2020 Nov 19.

Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University SE-75124 Uppsala Sweden

Solvent reorganization is a major driving force of protein-ligand association, but the contribution of binding site waters to ligand affinity is poorly understood. We investigated how altered interactions with a water network can influence ligand binding to a receptor. A series of ligands of the A adenosine receptor, which either interacted with or displaced an ordered binding site water, were studied experimentally and by molecular dynamics simulations. An analog of the endogenous ligand that was unable to hydrogen bond to the ordered water lost affinity and this activity cliff was captured by molecular dynamics simulations. Two compounds designed to displace the ordered water from the binding site were then synthesized and evaluated experimentally, leading to the discovery of an A agonist with nanomolar activity. Calculation of the thermodynamic profiles resulting from introducing substituents that interacted with or displaced the ordered water showed that the gain of binding affinity was enthalpy driven. Detailed analysis of the energetics and binding site hydration networks revealed that the enthalpy change was governed by contributions that are commonly neglected in structure-based drug optimization. In particular, simulations suggested that displacement of water from a binding site to the bulk solvent can lead to large energy contributions. Our findings provide insights into the molecular driving forces of protein-ligand binding and strategies for rational drug design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0sc04938gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179138PMC
November 2020

Nonoperative Rectal Cancer Management With Short-Course Radiation Followed by Chemotherapy: A Nonrandomized Control Trial.

Clin Colorectal Cancer 2021 09 7;20(3):e185-e193. Epub 2021 Apr 7.

Department of Radiation Oncology, University of Colorado School of Medicine, Denver, CO.

Purpose: Short-course radiation therapy (SCRT) and nonoperative management are emerging paradigms for rectal cancer treatment. This clinical trial is the first to evaluate SCRT followed by chemotherapy as a nonoperative treatment modality.

Methods: Patients with nonmetastatic rectal adenocarcinoma were treated on the single-arm, Nonoperative Radiation Management of Adenocarcinoma of the Lower Rectum study of SCRT followed by chemotherapy. Patients received 25 Gy in 5 fractions to the pelvis followed by FOLFOX ×8 or CAPOX ×5 cycles. Patients with clinical complete response (cCR) underwent nonoperative surveillance. The primary end point was cCR at 1 year. Secondary end points included safety profile and anorectal function.

Results: From June 2016 to March 2019, 19 patients were treated (21% stage I, 32% stage II, and 47% stage III disease). At a median follow-up of 27.7 months for living patients, the 1-year cCR rate was 68%. Eighteen of 19 patients are alive without evidence of disease. Patients with cCR versus without had improved 2-year disease-free survival (93% vs 67%; P = .006), distant metastasis-free survival (100% vs 67%; P = .03), and overall survival (100% vs 67%; P = .03). Involved versus uninvolved circumferential resection margin on magnetic resonance imaging was associated with less initial cCR (40% vs 93%; P = .04). Anorectal function by Functional Assessment of Cancer Therapy-Colorectal cancer score at 1 year was not different than baseline. There were no severe late effects.

Conclusions: Treatment with SCRT and chemotherapy resulted in high cCR rate, intact anorectal function, and no severe late effects. NCT02641691.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2021.03.003DOI Listing
September 2021

Mutation profile differences in younger and older patients with advanced breast cancer using circulating tumor DNA (ctDNA).

Breast Cancer Res Treat 2021 Feb 20;185(3):639-646. Epub 2020 Nov 20.

Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA.

Purpose: Little is known regarding the mutation profiles of ctDNA in the older adult breast cancer population. The objective of this study is to assess differences in mutation profiles in the older adult breast cancer population using a ctDNA assay as well as assess utilization of testing results.

Methods: Patients with advanced breast cancer underwent molecular profiling using a plasma-based ctDNA NGS assay (Guardant360) between 5/2015 and 10/2019 at Siteman Cancer Center. The profiling results of a multi-institutional database of patients with advanced breast cancer who had undergone molecular profiling were obtained. Associations between mutations and age group (≥ 65 vs. < 65) were examined using a Fisher's exact test.

Results: In the single-institutional cohort, 148 patients (69.2%) were < 65 years old and 66 patients (30.8%) ≥ 65 years old. ATM, BRAF, and PIK3CA mutations were found more frequently in older patients with ER + HER2- breast cancers (p < 0.01). In the multi-institutional cohort, 5367 (61.1%) were < 65 years old and 3417 (38.9%) ≥ 65 years old. ATM, PIK3CA, and TP53 mutations were more common in the older cohort (p < 0.0001) and MYC and GATA3 mutations were less common in the older cohort (p < 0.0001). CtDNA testing influenced next-line treatment management in 40 (19.8%) patients in the single-institutional cohort.

Conclusion: When controlling for subtype, results from a single institution were similar to the multi-institutional cohort showing that ATM and PIK3CA were more common in older adults. These data suggest there may be additional molecular differences in older adults with advanced breast cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-020-06019-0DOI Listing
February 2021

A phase I trial of temsirolimus and erlotinib in patients with refractory solid tumors.

Cancer Chemother Pharmacol 2021 03 6;87(3):337-347. Epub 2020 Nov 6.

Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.

Purpose: Resistance to treatment with inhibitors of mammalian target of rapamycin (mTOR) is partially mediated by activation of epidermal growth factor receptor (EGFR). We conducted a phase I study to determine the recommended phase II dose (RP2D) and dose-limiting toxicities (DLT) of temsirolimus (mTOR inhibitor) combined with erlotinib (EGFR inhibitor) in patients with refractory solid tumors.

Methods: Standard "3 + 3" design was used for dose escalation. An expansion cohort at RP2D included only patients with squamous histology or mutations relevant to PI3K or EGFR pathway activation. Patients started daily erlotinib 7 days prior to starting temsirolimus on cycle 1. Intravenous temsirolimus was then administered weekly. Starting dose levels were 15 mg for temsirolimus and 100 mg for erlotinib.

Results: Forty-four patients received treatment on this study (28 in dose escalation and 16 in the expansion cohort). The RP2D was temsirolimus 25 mg IV weekly and erlotinib 100 mg orally daily. Two patients experienced DLTs (G3 dehydration and G4 renal failure). The most common drug-related adverse events (all grades) were rash, mucositis/stomatitis, diarrhea, nausea and fatigue. No complete or partial responses were observed. The median duration on this study was 69 days (range 3-770) for escalation and 88 days (range 25-243) for expansion cohorts. Among 11 response-evaluable patients in the expansion cohort, 9 (82%) had stable disease and 2 (18%) had progressive disease.

Conclusion: The combination of temsirolimus and erlotinib at the RP2D was well tolerated, and the regimen resulted in prolonged disease stabilization in selected patients (NCT00770263).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-020-04183-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454489PMC
March 2021

Nucleotide P2Y receptor agonists are in vitro and in vivo prodrugs of A/A adenosine receptor agonists: implications for roles of P2Y and A/A receptors in physiology and pathology.

Purinergic Signal 2020 12 31;16(4):543-559. Epub 2020 Oct 31.

University of Texas Health at San Antonio, San Antonio, TX, USA.

Rapid phosphoester hydrolysis of endogenous purine and pyrimidine nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical nucleotide P2Y receptor (P2YR) agonists and antagonists. These included the riboside nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained (N)-methanocarba rings, which were previously reported to form nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A and AARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2YR activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to nucleotide agonists is due to AR activation by active nucleoside metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11302-020-09732-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855190PMC
December 2020

Design and in vivo activity of A adenosine receptor agonist prodrugs.

Purinergic Signal 2020 09 27;16(3):367-377. Epub 2020 Jul 27.

Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, 9000 Rockville Pike, Bethesda, MD, 20892-0810, USA.

Prodrugs (MRS7422, MRS7476) of highly selective A adenosine receptor (AR) agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2' and 3' hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known AAR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body AAR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked AAR agonists in models of two disease conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11302-020-09715-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524976PMC
September 2020

FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers: A Phase 2 Nonrandomized Clinical Trial.

JAMA Oncol 2020 08;6(8):1231-1240

Sylvester Comprehensive Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida.

Importance: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers.

Objective: To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma.

Design, Setting, And Participants: This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX.

Interventions: Starting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease.

Main Outcomes And Measures: The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response.

Results: From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects.

Conclusions And Relevance: The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status.

Trial Registration: ClinicalTrials.gov Identifier: NCT01928290.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260693PMC
August 2020

Allosteric Antagonism of the A Adenosine Receptor by a Series of Bitopic Ligands.

Cells 2020 05 12;9(5). Epub 2020 May 12.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A adenosine receptor (AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed K binding values consistent with K values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(,-hexamethylene)amiloride (HMA) were 9-100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9051200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290864PMC
May 2020

Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma.

J Gastrointest Oncol 2020 Feb;11(1):61-67

Department of Internal Medicine, Division of Medical Oncology, Washington University in St. Louis, St. Louis, MO, USA.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC.

Methods: We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m oral twice-daily days 1-14 and oral tosedostat in a dose de-escalation design on days 1-21 of each 21-day cycle. Primary endpoints were the recommended phase 2 dose (RP2D) and progression-free survival (PFS).

Results: Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m oral twice daily was the RP2D. There was one dose-limiting toxicity (DLT) (grade 3 acute coronary syndrome) during phase Ib. The most common treatment-related adverse events were gastrointestinal (nausea, diarrhea), cardiac [QTc prolongation, decreased ejection fraction (EF)], and fatigue. The median PFS was 7.1 months, and the median treatment failure free survival was 3 months. Eight patients experienced stable disease for greater than 3 months. The study was closed early due to lack of drug availability.

Conclusions: Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo.2019.11.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052765PMC
February 2020

Randomized controlled trial of high-dose versus standard-dose vitamin D3 for prevention of aromatase inhibitor-induced arthralgia.

Breast Cancer Res Treat 2019 Sep 19;177(2):427-435. Epub 2019 Jun 19.

Baylor College of Medicine, 6445 Main Street, OPC 24-346, Houston, TX, 77030, USA.

Purpose: Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment.

Methods: We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled.

Results: The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development.

Conclusion: Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-019-05319-4DOI Listing
September 2019

Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and Subsequent Regimens in Metastatic Breast Cancer.

J Natl Compr Canc Netw 2019 02;17(2):141-147

aWashington University School of Medicine, and.

Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of care for hormone receptor-positive (HR+), HER2-negative (HER-) metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study examines physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. A retrospective chart review was conducted for consecutive patients with MBC who received palbociclib between February 2015 and August 2017 at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. A total of 200 patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), and the fraction of patients receiving palbociclib as first- or second-line therapy increased in recent months (=.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively (<.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to reports in the literature. Among patients whose disease progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination with targeted agents (n=32) after first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively (=.04). mPFS with chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-, and subsequent-line palbociclib, respectively (=.56). Palbociclib is effective for HR+/HER2- MBC in real-world practice. Hormone therapy alone or in combination with targeted agents remains an effective option after palbociclib progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2018.7094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752198PMC
February 2019

Activation of adenosine A or A receptors causes hypothermia in mice.

Neuropharmacology 2018 09 13;139:268-278. Epub 2018 Mar 13.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

Extracellular adenosine is a danger/injury signal that initiates protective physiology, such as hypothermia. Adenosine has been shown to trigger hypothermia via agonism at A and A adenosine receptors (AAR, AAR). Here, we find that adenosine continues to elicit hypothermia in mice null for AAR and AAR and investigated the effect of agonism at AAR or AAR. The poorly brain penetrant AAR agonists CGS-21680 and PSB-0777 caused hypothermia, which was not seen in mice lacking AAR. MRS7352, a likely non-brain penetrant AAR antagonist, inhibited PSB-0777 hypothermia. While vasodilation is probably a contributory mechanism, AAR agonism also caused hypometabolism, indicating that vasodilation is not the sole mechanism. The AAR agonist BAY60-6583 elicited hypothermia, which was lost in mice null for AAR. Low intracerebroventricular doses of BAY60-6583 also caused hypothermia, indicating a brain site of action, with neuronal activation in the preoptic area and paraventricular nucleus of the hypothalamus. Thus, agonism at any one of the canonical adenosine receptors, AAR, AAR, AAR, or AAR, can cause hypothermia. This four-fold redundancy in adenosine-mediated initiation of hypothermia may reflect the centrality of hypothermia as a protective response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2018.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067974PMC
September 2018

Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer.

J Gastrointest Oncol 2017 Dec;8(6):985-989

Division of Oncology, University of Miami, Miami, FL, USA.

Background: Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma.

Methods: A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment. Pacritinib 400 mg daily was administered orally continuously in 28 day cycles.

Results: The trial was discontinued prior to reaching the planned accrual due to an FDA hold on pacritinib and a lack of treatment benefit. Eleven patients were enrolled and seven were evaluated for response. Median baseline C-reactive protein level was 12.1 (2.1-147) mg/L. One patient had stable disease at eight weeks by RECIST criteria and six progressed. There were no grade 4 or 5 adverse events while patients were on study. The grade 2 and lower AE events experienced were consistent with prior pacritinib trials.

Conclusions: In seven evaluable patients there were no objective responses. The trial was discontinued prior to completing planned accrual based on a low likelihood that the progression free survival goal of 4 months would be met.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo.2017.08.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750170PMC
December 2017

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer.

Clin Cancer Res 2017 Aug 7;23(15):4055-4065. Epub 2017 Mar 7.

Pfizer Pharmaceuticals, New York, New York.

Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Eligible patients with clinical stage II/III ER/HER2 breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-16-3206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555232PMC
August 2017

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.

Lancet Oncol 2016 05 4;17(5):651-62. Epub 2016 Apr 4.

Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA; Center for Tumor Immunology, University of Rochester Medical Center, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. Electronic address:

Background: In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil).

Methods: We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022.

Results: Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease.

Interpretation: CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable.

Funding: Washington University-Pfizer Biomedical Collaborative.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(16)00078-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407285PMC
May 2016

A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.

Clin Cancer Res 2016 Apr 12;22(7):1583-91. Epub 2015 Nov 12.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Purpose: This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER(+)) breast cancer.

Experimental Design: Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts.

Results: Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%-74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations inAKT1 and ESR1 did not exclude treatment response.

Conclusions: Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER(+)breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-15-1745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818722PMC
April 2016

A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma.

HPB (Oxford) 2015 Jul 20;17(7):587-93. Epub 2015 Mar 20.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Objectives: Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated.

Methods: After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS).

Results: Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively.

Conclusions: This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hpb.12413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474505PMC
July 2015

Carbamoylphosphonates inhibit autotaxin and metastasis formation in vivo.

J Enzyme Inhib Med Chem 2015 11;30(5):767-72. Epub 2015 Feb 11.

a Institute for Drug Research , Hebrew University of Jerusalem , Jerusalem , Israel and.

Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC(6)H(4)SO(2)NH(CH(2))nNHCOPO(3)H(2), with increasing lengths of methylene chains, (CH(2))(n), n = 4-8. Carbamoylphosphonates having n = 6, 7, 8 inhibited autotaxin in vitro with IC(50) ≈ 1.5 µM. Using an imaging probe we demonstrated that compound n = 6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound n = 7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/14756366.2014.968146DOI Listing
May 2016

A phase I study of pegylated liposomal doxorubicin and temsirolimus in patients with refractory solid malignancies.

Cancer Chemother Pharmacol 2014 Aug 11;74(2):419-26. Epub 2014 Jun 11.

Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA.

This study aimed to determine the maximum-tolerated dose and dose-limiting toxicities of pegylated liposomal doxorubicin (PLD) in combination with temsirolimus (T) in patients with refractory solid tumors. Using a standard "3+3" dose escalation design, 23 patients were enrolled in three dosing cohorts in this phase I study. The starting dose level was PLD at 30 mg/m(2) every 4 weeks and T at 20 mg weekly. Pharmacokinetics (PK) of doxorubicin were evaluated for patients in the expansion cohort. The most common treatment-related adverse events of all grades were mucositis/stomatitis (69.6%), anorexia (52.2%), thrombocytopenia (52.2%), and fatigue (47.8%). The recommended doses of this combination for phase II studies are 25 mg/m(2) PLD and 25 mg T. PK analyses suggested increased exposure of doxorubicin in this combination regimen compared to doxorubicin administered as a single agent, possibly due to PK drug interactions. Out of 18 patients evaluable for a treatment response, two had partial responses (PR) (breast cancer and hepatocellular carcinoma) and six had stable disease (SD). Two patients remained on treatment for more than 1 year. The combination of PLD and T is tolerable, and the treatment resulted in clinical benefit. The combination regimen should be further explored in appropriate tumor types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-014-2493-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112045PMC
August 2014

Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for rectal cancer.

Int J Radiat Oncol Biol Phys 2014 Mar;88(4):829-36

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

Background: Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy.

Methods And Materials: Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of FOLFOX [5-fluorouracil, oxaliplatin, leucovorin]. Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls.

Results: 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%).

Conclusion: This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2013.12.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028157PMC
March 2014

Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts.

Cell Rep 2013 Sep 19;4(6):1116-30. Epub 2013 Sep 19.

Section of Breast Oncology, Division of Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center Breast Cancer Program, Washington University in St. Louis, St. Louis, MO 63110, USA.

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2013.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881975PMC
September 2013

Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma.

JOP 2012 Sep 10;13(5):497-501. Epub 2012 Sep 10.

Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.

Context: Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial.

Objective: The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists.

Methods: Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications.

Results: Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events.

Conclusion: Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6092/1590-8577/913DOI Listing
September 2012

A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma.

Invest New Drugs 2013 Jun 4;31(3):707-13. Epub 2012 Aug 4.

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Purpose: This phase I study was conducted to determine the safety profile and maximum tolerated dose (MTD) of IMP321, a soluble lymphocyte activation gene-3 (LAG-3) Ig fusion protein and MHC Class II agonist, combined with gemcitabine in patients with advanced pancreatic adenocarcinoma.

Patients And Methods: Patients with advanced pancreatic adenocarcinoma were treated with gemcitabine (1,000 mg/m(2))(level 1), gemcitabine (1,000 mg/m(2)) plus IMP 321 at 0.5 mg (level 2) and 2.0 mg (level 3), respectively. Safety, toxicity, and immunological markers at baseline and post treatment were assessed.

Results: A total of 18 patients were enrolled to the study, and 17 were evaluable for toxicity. None of the 6 patients who received 0.5 mg IMP321 experienced IMP321-related adverse events. Of the 5 patients who received IMP321 at the 2 mg dose level, 1 experienced rash, 1 reported hot flashes and 2 had mild pain at the injection sites. No severe adverse events previously attributed to IMP321 were observed. No significant differences were observed when comparing pre- and post-treatment levels of monocytes (CD11b+CD14+), conventional dendritic cells (CD11c+) or T cell subsets (CD4, CD8).

Conclusions: IMP321 in combination with gemcitabine is a well-tolerated regimen. IMP321 did not result in any severe adverse events. No incremental activity observed for the additional IMP 321 to gemcitabine at the dose levels evaluated, likely due to sub-optimal dosing. Immunological markers suggested that higher dose levels of IMP321 are needed for future clinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10637-012-9866-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760728PMC
June 2013
-->