Publications by authors named "Shilpa Gupta"

109 Publications

Treatment-induced Treatment Sensitization in Metastatic Castration-resistant Prostate Cancer.

Eur Urol 2021 Feb 16. Epub 2021 Feb 16.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2021.02.004DOI Listing
February 2021

Quantification and Optimization of Standard-of-Care Therapy to Delay the Emergence of Resistant Bone Metastatic Prostate Cancer.

Cancers (Basel) 2021 Feb 8;13(4). Epub 2021 Feb 8.

Integrated Mathematical Oncology Department, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Background: Bone metastatic prostate cancer (BMPCa), despite the initial responsiveness to androgen deprivation therapy (ADT), inevitably becomes resistant. Recent clinical trials with upfront treatment of ADT combined with chemotherapy or novel hormonal therapies (NHTs) have extended overall patient survival. These results indicate that there is significant potential for the optimization of standard-of-care therapies to delay the emergence of progressive metastatic disease.

Methods: Here, we used data extracted from human bone metastatic biopsies pre- and post-abiraterone acetate/prednisone to generate a mathematical model of bone metastatic prostate cancer that can unravel the treatment impact on disease progression. Intra-tumor heterogeneity in regard to ADT and chemotherapy resistance was derived from biopsy data at a cellular level, permitting the model to track the dynamics of resistant phenotypes in response to treatment from biological first-principles without relying on data fitting. These cellular data were mathematically correlated with a clinical proxy for tumor burden, utilizing prostate-specific antigen (PSA) production as an example.

Results: Using this correlation, our model recapitulated the individual patient response to applied treatments in a separate and independent cohort of patients (n = 24), and was able to estimate the initial resistance to the ADT of each patient. Combined with an intervention-decision algorithm informed by patient-specific prediction of initial resistance, we propose to optimize the sequence of treatments for each patient with the goal of delaying the evolution of resistant disease and limit cancer cell growth, offering evidence for an improvement against retrospective data.

Conclusions: Our results show how minimal but widely available patient information can be used to model and track the progression of BMPCa in real time, offering a clinically relevant insight into the patient-specific evolutionary dynamics of the disease and suggesting new therapeutic options for intervention.

Trial Registration: NCT # 01953640.

Funding: Funded by an NCI U01 (NCI) U01CA202958-01 and a Moffitt Team Science Award. CCL and DB were partly funded by an NCI PSON U01 (U01CA244101). AA was partly funded by a Department of Defense Prostate Cancer Research Program (W81XWH-15-1-0184) fellowship. LC was partly funded by a postdoctoral fellowship (PF-13-175-01-CSM) from the American Cancer Society.
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http://dx.doi.org/10.3390/cancers13040677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915310PMC
February 2021

Defining cisplatin eligibility in patients with muscle-invasive bladder cancer.

Nat Rev Urol 2021 Feb 11;18(2):104-114. Epub 2021 Jan 11.

Division of Medical Oncology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

The current treatment paradigm for muscle-invasive bladder cancer (MIBC) consists of cisplatin-based neoadjuvant chemotherapy followed by local definitive therapy, or local definitive therapy alone for cisplatin-ineligible patients. Given that MIBC has a high propensity for distant relapse and is a chemotherapy-sensitive disease, under-utilization of chemotherapy is associated with suboptimal cure rates. Cisplatin eligibility criteria are defined for patients with metastatic bladder cancer by the Galsky criteria, which include creatinine clearance ≥60 ml/min. However, consensus is still lacking regarding cisplatin eligibility criteria in the neoadjuvant, curative MIBC setting, which continues to represent a substantial barrier to the standardization of patient care and clinical trial design. Jiang and colleagues accordingly suggest an algorithm for assessing cisplatin eligibility in patients with MIBC. Instead of relying on an absolute renal function threshold, their algorithm emphasizes a multidisciplinary and patient-centred approach. They also propose mitigation strategies to minimize the risk of cisplatin-induced nephrotoxicity in selected patients with impaired renal function. This new framework is aimed at reducing the inappropriate exclusion of some patients from cisplatin-based neoadjuvant chemotherapy (which leads to under-treatment) and harmonizing clinical trial design, which could lead to improved overall outcomes in patients with MIBC.
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http://dx.doi.org/10.1038/s41585-020-00404-6DOI Listing
February 2021

Abiraterone acetate in combination with androgen deprivation therapy compared to androgen deprivation therapy only for metastatic hormone-sensitive prostate cancer.

Cochrane Database Syst Rev 2020 12 12;12:CD013245. Epub 2020 Dec 12.

Department of Urology, University Hospital Erlangen, Erlangen, Germany.

Background: Systemic androgen deprivation therapy (ADT), also referred to as hormone therapy,àhas long been the primary treatment for metastatic prostate cancer. Additional agents have been reserved for the castrate-resistant disease stage when ADT start becoming less effective. Abiraterone is an agent with an established role in that disease stage, which has only recently been evaluated in the hormone-sensitive setting.

Objectives: To assess the effects of early abiraterone acetate, in combination with systemic ADT, for newly diagnosed metastatic hormone-sensitive prostate cancer.

Search Methods: We searched CENTRAL, MEDLINE, Embase, six other databases, two trials registries, grey literature, and conference proceedings, up to 15 May 2020. We applied no restrictions on publication language or status.

Selection Criteria: We included randomized trials, in which men diagnosed with hormone-sensitive prostate cancer were administered abiraterone acetate and prednisolone with ADT or ADTàalone.

Data Collection And Analysis: Two review authors independently classified studies and abstracted data from the included studies. We performed statistical analyses using a random-effects model. We rated the quality of evidence according to the GRADE approach.

Main Results: The search identified two randomized controlled trials (RCT), with 2201 men, who were assigned to receive either abiraterone acetate 1000 mg once daily and low dose prednisone (5mg) in addition to ADT, or ADT alone. In the LATITUDE trial, the median age and range of men in the intervention group was 68 (38 to 89) years, and 67 (33 to 92) years in the control group. Nearly all of the men in thisàstudy (97.6%) had prostate cancer with a Gleason score of at least 8 (ISUP grade group 4). Primary outcomes The addition of abiraterone acetate to ADT reduces the probability of death from any cause compared to ADT alone (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.56 to 0.73; 2 RCTs, 2201 men; high certainty of evidence); this corresponds to 163 fewer deaths per 1000 men with hormone-sensitive metastaticàprostate cancerà(210 fewer to 115 fewer) at five years. Abiraterone acetate in addition to ADT probably results in little to no differenceàin quality of life compared to ADT alone, measured with the Functional Assessment of Cancer Therapy-prostate total score (FACT-P; range 0 to 156; higher values indicates better quality of life),àat 12 months (mean difference [MD] 2.90 points, 95% CI 0.11 to 5.60; 1 RCT, 838 men; moderate certainty of evidence). Secondary outcomes Abiraterone plus ADT increases the risk of grades III to V adverse events compared to ADT alone (risk ratio [RR] 1.34, 95% CI 1.22 to 1.47; 1 RCT, 1199 men; high certainty of evidence); this corresponds to 162 more grade III to Vàevents per 1000 men with hormone-sensitive metastaticàprostate cancerà(105 more to 224 more) at a median follow-up of 30àmonths. Abiraterone acetate in addition to ADT probably reduces the probability of death due to prostate cancer compared to ADT alone (HR 0.58, 95% CI 0.50 to 0.68; 2 RCTs, 2201 men; moderate certainty of evidence). This corresponds to 120 fewer death from prostate cancer per 1000 men with hormone-sensitive metastaticàprostate cancerà(95% CI 145 fewer to 90 fewer) afteràa median follow-up of 30 months. The addition of abiraterone acetate to ADT probably decreases the probability of disease progression compared to ADT alone (HR 0.35, 95%CI 0.26 to 0.49; 2 RCTs, 2097 men; moderate certainty of evidence). This corresponds to 369 fewer incidences of disease progression per 1000 men with hormone-sensitive metastaticàprostate cancerà(456 fewer to 256 fewer)àafter a median follow-up of 30 months. The addition of abiraterone acetate to ADT probably increases the risk of discontinuing treatment due to adverse events compared to ADT alone (RR 1.50, 95% CI 1.17 to 1.92; 1 RCT, 1199 men; moderate certainty of evidence). This corresponds to 51 more men (95% CI 17 more to 93 more) discontinuing treatment because of adverse events per 1000 men treated with abiraterone acetate and ADT compared to ADT alone afteràa median follow-up of 30 months.

Authors' Conclusions: The addition of abiraterone acetate to androgen deprivation therapy improves overall survival but probably not quality of life. Itàprobably also extends disease-specific survival, and delays disease progression compared to androgen deprivation therapy alone. However, the risk of grades III to V adverse events is increased, and probably, so is the risk of discontinuing treatment due to adverse events.
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http://dx.doi.org/10.1002/14651858.CD013245.pub2DOI Listing
December 2020

Conformational properties of complexes of poly(propylene imine) dendrimers with linear polyelectrolytes in dilute solutions.

J Chem Phys 2020 Nov;153(19):194902

Department of Chemistry, University of Delhi, Delhi 110007, India.

This study investigates the conformational properties of complexes of poly(propylene imine) dendrimers with a linear polyelectrolyte (LPE) at neutral pH in an aqueous solution via molecular dynamics simulations. Various conformational properties, such as the atomic density profile, counterion density distribution, charge distribution, cavity volume, and the static structure factor are studied as a function of the charge and chain length of the LPE. The lower generation dendrimer complexes encapsulate the shorter linear PE chains, while the longer PE chains are adsorbed on the dendrimer surface that screen the surface charge and prevent the penetration of the counterions and water molecules. However, the overall charge of the higher generation dendrimers is not neutralized by the charge of the PE chains, which results in chloride counterion penetration within the dendrimers. The adsorption of the PE chains on the dendrimers is also verified from the charge distribution of the dendrimer-PE complexes. The charge on the lower generation dendrimer complexes is overcompensated by the longer PE chains resulting in an overall negative charge on the complexes, while the PE chains do not completely neutralize the charge of the higher generation dendrimers and produce positively charged complexes. The results of the structure factor indicate a conformational transition of the dendrimer-PE complexes from a dense compact structure to an open one with an increase in the PE chain length. This transition is characterized by an increase in the cavity volume in dendrimers with an increase in the PE chain length.
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http://dx.doi.org/10.1063/5.0030270DOI Listing
November 2020

Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors.

J Immunother Cancer 2020 10;8(2)

Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.

Patients And Methods: Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005-0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.

Results: From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.

Conclusion: IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.

Trial Registration Number: NCT02556463.
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http://dx.doi.org/10.1136/jitc-2020-001095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549442PMC
October 2020

Practical Considerations and Challenges for Germline Genetic Testing in Patients With Prostate Cancer: Recommendations From the Germline Genetics Working Group of the PCCTC.

JCO Oncol Pract 2020 Dec 28;16(12):811-819. Epub 2020 Sep 28.

Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, CA.

Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited access to genetics providers. This suggests a critical unmet need for genetic services outside of historical models. This review addresses current guidelines, considerations, and challenges for PCa genetic testing and offers a practical guide for genetic counseling and testing delivery, with solutions to help address potential barriers and challenges for both providers and patients. As genetic and genomic testing become integral to PCa care, developing standardized systems for implementation in the clinic is essential for delivering precision oncology to patients with PCa and realizing the full scope and impact of genetic testing.
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http://dx.doi.org/10.1200/OP.20.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735040PMC
December 2020

Sex Differences in Bladder Cancer Immunobiology and Outcomes: A Collaborative Review with Implications for Treatment.

Eur Urol Oncol 2020 10 20;3(5):622-630. Epub 2020 Sep 20.

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; Department of Urology, Queen's University, Kingston, Ontario, Canada.

Context: Urothelial carcinoma of the bladder (UCB) exhibits significant sexual dimorphism in the incidence, etiology, and response to intravesical immunotherapy. Environmental factors such as tobacco use and clinical management issues such as delayed presentation have widely been associated with sex differences in UCB outcomes. Emerging findings from immune checkpoint blockade trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in the way immune system functions and responds to pathogenic insults are well established. As such, an in-depth understanding of the genetic and epigenetic factors contributing to sex-associated differences in response to immunomodulatory therapies is needed urgently for improved management of UCB.

Objective: To review the associations between patient sex and clinical outcomes, with a focus on the incidence, host intrinsic features, and response to therapies in UCB.

Evidence Acquisition: Using the PubMed database, this narrative review evaluates published findings from mouse model-based and clinical cohort studies to identify factors associated with sex and clinical outcomes in bladder cancer. A scoping review of the key findings on epidemiology, genetic, hormonal, immune physiology, and clinical outcomes was performed to explore potential factors that could have implications in immunomodulatory therapy design.

Evidence Synthesis: Sex-associated differences in UCB incidence and clinical outcomes are influenced by sex hormones, local bladder resident immune populations, tumor genetics, and bladder microbiome. In the context of therapeutic outcomes, sex differences are prominent in response to bacillus Calmette-Guérin immunotherapy used in the treatment of non-muscle-invasive bladder cancer. Similarly, with respect to tumor molecular profiles in muscle-invasive bladder cancer, tumors from females show enrichment of the basal subtype.

Conclusions: Among proposed tumor/host intrinsic factors that may influence response to immune-based therapies, patient sex remains a challenging consideration that deserves further attention. Evidence to date supports a multifactorial origin of sexual dimorphism in the incidence and outcomes of UCB.

Patient Summary: In this review, we highlight the sex-associated host and tumor intrinsic features that may potentially drive differential disease progression and therapeutic response in urothelial carcinoma of the bladder.
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http://dx.doi.org/10.1016/j.euo.2020.08.013DOI Listing
October 2020

Abrogating ALIX Interactions Results in Stuttering of the ESCRT Machinery.

Viruses 2020 09 16;12(9). Epub 2020 Sep 16.

Center for Cell and Genome Sciences, University of Utah, Salt Lake City, UT 84112, USA.

Endosomal sorting complexes required for transport (ESCRT) proteins assemble on budding cellular membranes and catalyze their fission. Using live imaging of HIV virions budding from cells, we followed recruitment of ESCRT proteins ALIX, CHMP4B and VPS4. We report that the ESCRT proteins transiently co-localize with virions after completion of virion assembly for durations of 45 ± 30 s. We show that mutagenizing the YP domain of Gag which is the primary ALIX binding site or depleting ALIX from cells results in multiple recruitments of the full ESCRT machinery on the same virion (referred to as stuttering where the number of recruitments to the same virion >3). The stuttering recruitments are approximately 4 ± 3 min apart and have the same stoichiometry of ESCRTs and same residence time (45 ± 30 s) as the single recruitments in wild type interactions. Our observations suggest a role for ALIX during fission and question the linear model of ESCRT recruitment, suggesting instead a more complex co-assembly model.
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http://dx.doi.org/10.3390/v12091032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551432PMC
September 2020

High-speed imaging of ESCRT recruitment and dynamics during HIV virus like particle budding.

PLoS One 2020 4;15(9):e0237268. Epub 2020 Sep 4.

Center for Cell and Genome Science, University of Utah, Salt Lake City, Utah, United States of America.

Endosomal sorting complexes required for transport proteins (ESCRT) catalyze the fission of cellular membranes during budding of membrane away from the cytosol. Here we have used Total Internal Reflection Fluorescence (TIRF) microscopy to visualize the recruitment of ESCRTs specifically, ALIX, CHMP4b and VPS4 onto the budding HIV Gag virus-like particles (VLPs). We imaged the budding VLPs with 200 millisecond time resolution for 300 frames. Our data shows three phases for ESCRT dynamics: 1) recruitment in which subunits of ALIX, CHMP4b and VPS4 are recruited with constant proportions on the budding sites of HIV Gag virus like particles for nearly 10 seconds, followed by 2) disassembly of ALIX and CHMP4b while VPS4 signal remains constant for nearly 20 seconds followed by 3) disassembly of VPS4. We hypothesized that the disassembly observed in step 2 was catalyzed by VPS4 and powered by ATP hydrolysis. To test this hypothesis, we performed ATP depletion using (-) glucose medium, deoxyglucose and oligomycin. Imaging ATP depleted cells, we show that the disassembly of CHMP4b and ALIX observed in step 2 is ATP dependent. ATP depletion resulted in the recruitment of approximately 2-fold as many subunits of all ESCRTs. Resuming ATP production in cells, resulted in disassembly of the full ESCRT machinery which had been locked in place during ATP depletion. With some caveats, our experiments provide insight into the formation of the ESCRT machinery at the budding site of HIV during budding.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237268PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473513PMC
October 2020

Conformations of poly(propylene imine) dendrimers in an ionic liquid at different pH.

Soft Matter 2020 Sep;16(36):8400-8411

Department of Chemistry, University of Delhi, Delhi-110007, India.

The conformational behavior of poly(propylene imine) (PPI) dendrimers at three different solution pH is studied in an ionic liquid (IL) solvent, 1-butyl-3-methylimidazolium chloride ([BMIM]Cl), through molecular dynamics (MD) simulations. The size, shape, density distribution, structure factor, and the scattering intensity are evaluated to probe the conformational transition of dendrimers as a function of pH. The results of the radial atomic and terminal amine group density distribution at low pH indicate a shift in the density towards the periphery of the dendrimers due to the electrostatic repulsion between the charged tertiary amine groups within the dendrimers. The [BMIM] cations are not encapsulated within dendrimers and predominantly reside near the periphery. The extensive back-folding of the outer branches due to the electrostatic repulsion between the solvent cations and the peripheral charged amine groups at neutral and low pH results in a dense compact structure in [BMIM]Cl as compared to that in water, as evident from the results of the structure factor and scattering intensity. The structural analysis in terms of the fractal dimension reveals that the lower generation dendrimers exhibit conformational transition as a function of pH, while the higher generations exhibit a highly compact structure at all solution pH. However, PPI dendrimers at low pH exhibit more free volume as compared to that at high pH, which may be utilized to accommodate specific guest molecules.
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http://dx.doi.org/10.1039/d0sm01026jDOI Listing
September 2020

Androgen receptor in bladder cancer: A promising therapeutic target.

Asian J Urol 2020 Jul 2;7(3):284-290. Epub 2020 Jun 2.

Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.

There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades. While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma, unfortunately, only a minority of patients respond to immunotherapy. Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma. The first targeted therapy targeting the fibroblast growth factor receptor (FGFR) was recently approved for bladder cancer, but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations. Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials. Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer. Exploitation of androgen receptor (AR) is a potential strategy for targeted drug development in bladder cancer. A significant proportion of urothelial carcinoma patients express AR irrespective of gender. AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms, including activation of human epidermal growth factor receptor-2 (EGFR or HER-2) signaling and epithelial to mesenchymal transition (EMT). Furthermore, AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy. Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy. We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis, progression and its role as a novel therapeutic target and future directions.
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http://dx.doi.org/10.1016/j.ajur.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385521PMC
July 2020

Author Correction: NICE's rejection of pembrolizumab for platinum-refractory urothelial carcinoma: is there a greater good?

Nat Rev Urol 2020 Sep;17(9):540

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41585-020-0361-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608133PMC
September 2020

Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Cancer Discov 2020 10 22;10(10):1514-1527. Epub 2020 Jul 22.

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. SIGNIFICANCE: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541683PMC
October 2020

NICE's rejection of pembrolizumab for platinum-refractory urothelial carcinoma: is there a greater good?

Nat Rev Urol 2020 Sep;17(9):491-492

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1038/s41585-020-0357-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338128PMC
September 2020

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

Lancet 2020 06 28;395(10241):1907-1918. Epub 2020 May 28.

Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Background: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.

Methods: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.

Findings: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.

Interpretation: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.

Funding: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.
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http://dx.doi.org/10.1016/S0140-6736(20)31187-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255743PMC
June 2020

Orientational Relaxation of Poly(propylene imine) Dendrimers at Different pH.

J Phys Chem B 2020 05 8;124(20):4193-4202. Epub 2020 May 8.

Department of Chemistry, University of Delhi, Delhi 110007, India.

The dilute solution dynamics of poly(propylene imine) (PPI) dendrimers is investigated at three different solution pH through molecular dynamics (MD) simulations. The dynamics of PPI dendrimers is characterized by both global and local relaxations that occur at different time and length scales. While the global dynamics may be described in terms of rotational diffusion, the local motion may be characterized through orientational relaxation dynamics measured in terms of the time autocorrelation function (ACF), second-order orientational ACF, and the spin-lattice relaxation rate. The global motion of dendrimers decreases with an increase in the size from high pH to low pH with increasing generations of growth. The results reveal that the segments at low pH relax faster than those at high pH, and the local mobility of the segments near the periphery is higher than the core segments. This observation is also evident from the spectral density and spin-lattice relaxation rate. High values of the spectral density at higher frequencies imply higher segmental mobility of the dendrimer at low pH relative to that at high pH. A shift in the maximum of the spin-lattice relaxation rate toward lower frequencies with decreasing generations indicates the dependence of local mobility on the topological distance of the segment from the periphery at all pH conditions.
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http://dx.doi.org/10.1021/acs.jpcb.0c00536DOI Listing
May 2020

Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer.

J Clin Oncol 2020 06 9;38(16):1797-1806. Epub 2020 Apr 9.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA.

Purpose: Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons.

Patients And Methods: Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS).

Results: Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank = .04; maximum efficiency robust test = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival.

Conclusion: Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.
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http://dx.doi.org/10.1200/JCO.19.03091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983PMC
June 2020

Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce.

J Immunother Cancer 2020 03;8(1)

Massachusetts General Hospital, Boston, MA, United States

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce-consisting of experts in cancer immunotherapy from academia, industry, and government-to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.
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http://dx.doi.org/10.1136/jitc-2019-000398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174063PMC
March 2020

Dipsacus inermis Wall. modulates inflammation by inhibiting NF-κB pathway: An in vitro and in vivo study.

J Ethnopharmacol 2020 May 22;254:112710. Epub 2020 Feb 22.

Department of Biochemistry, University of Kashmir, J&K, 190006, India. Electronic address:

Ethnopharmacological Relevance: Dipsacus inermis Wall. is an edible Himalayan herb which is extensively used in traditional Ayurvedic system of medicine against various inflammation related disorders.

Aim Of The Study: This study was designed to evaluate the anti-inflammatory effects of Dipsacus inermis Wall. methanol extract (DIME) by using in vitro and in vivo models and to elucidate the underlying mechanism of action.

Materials And Methods: The in vitro anti-inflammatory potential of DIME was determined in LPS stimulated J774A.1 cells. The inhibitory effect of DIME on COX-2, PGE2 and inflammatory cytokines was determined by ELISA and RT-PCR. The suppression of ROS in response to DIME was determined by flow cytometry. Phosphorylation of NF-κBp65 and IκB degradation was determined by western blotting.

Results: Significant inhibition of NO, COX-2, PGE2 and pro-inflammatory cytokines including IL-1β, TNF-α and IL-6 was found in response to DIME in LPS stimulated J774A.1 cells. The extract was found to down regulate the LPS induced expression of TNF-α, IL-6, iNOS and COX-2 along with inhibition of intracellular ROS. The in vivo studies carried on Wistar rats showed significant preventive effect of DIME against acetic acid induced increase in vascular permeability and carrageenan induced paw edema along with stabilization of histopathological alterations.

Conclusion: The study demonstrated that DIME has significant in vitro and in vivo anti-inflammatory effect which is mediated by inhibiting the activation of NF-κB pathway. Our data opened a promising new pharmacological approach of designing anti-inflammatory drugs by studying individual fractions of the plant extract.
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http://dx.doi.org/10.1016/j.jep.2020.112710DOI Listing
May 2020

Phase Ib/II Clinical Trial of Pembrolizumab With Bevacizumab for Metastatic Renal Cell Carcinoma: BTCRC-GU14-003.

J Clin Oncol 2020 04 25;38(11):1138-1145. Epub 2020 Feb 25.

Rogel Cancer Center, University of Michigan, Ann Arbor, MI.

Purpose: We hypothesized that bevacizumab will potentiate activity of pembrolizumab. We conducted a phase Ib/II, single-arm, multisite clinical trial of the combination in metastatic renal cell carcinoma (RCC).

Patients And Methods: Patients with metastatic clear cell RCC who experienced progression after at least one systemic therapy (phase Ib) or were treatment naïve (phase II) were enrolled. In phase Ib, pembrolizumab (200 mg) and bevacizumab (10 or 15 mg/kg) were given intravenously every 3 weeks. The primary end point for phase II was overall response rate (ORR). With an 80% statistical power and a type I error probability of 0.1, 48 patients were to be accrued to detect an ORR of 42%.

Results: Thirteen patients (ages 33-68 years; median, 55 years) were enrolled in the phase Ib study. No dose-limiting toxicities were reported. Pembrolizumab 200 mg and bevacizumab 15 mg/kg were chosen for phase II. Forty-eight patients (ages 42-84 years; median age, 61 years; 33 males) were accrued for the phase II study. The primary end point was met, with the ORR reaching 60.9% (95% CI, 45.4% to 74.9%), consisting of 1 complete response (CR), 2 CRs in target lesions, 25 partial responses, 18 responses of stable disease, 2 unevaluable responses. Median progression-free survival was 20.7 months (95% CI, 11.3 to 27.4 months). Median overall survival was not reached at the median follow-up of 28.3 months. The most common treatment-related grade 3 toxicities were hypertension and proteinuria. There were two grade 4 toxicities: duodenal ulcer and hyponatremia. Presence of tumor-infiltrating T cells, but not programmed death-ligand 1 expression, in tumor tissue correlated with response.

Conclusion: The combination of 200 mg of pembrolizumab and a 15 mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC.
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http://dx.doi.org/10.1200/JCO.19.02394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145584PMC
April 2020

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer.

Future Oncol 2020 Jan 11;16(2):4359-4368. Epub 2019 Dec 11.

Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.
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http://dx.doi.org/10.2217/fon-2019-0611DOI Listing
January 2020

Immuno-Oncology Approaches to Salvage Treatment for Non-muscle invasive Bladder Cancer.

Urol Clin North Am 2020 Feb;47(1):103-110

Department of Urology, University of Minnesota, 420 Delaware Street Southeast, MMC 394, Minneapolis, MN, USA.

This article provides a comprehensive review of the available data for immunotherapy being used as a salvage treatment in non-muscle-invasive bladder cancer. The literature demonstrates that the immune system has an important role in bladder cancer progression. Initial results from studies using checkpoint inhibitors, recombinant interferon-α2b protein, and oncolytic adenoviruses have shown promising responses with acceptable toxicities. However, the majority of the current data arises from small trials with limited follow-up. There are currently several ongoing studies in this setting, which we await completion, to increase our understanding of immunotherapy as a salvage treatment in non-muscle-invasive bladder cancer.
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http://dx.doi.org/10.1016/j.ucl.2019.09.012DOI Listing
February 2020

Exploitation of CD133 for the Targeted Imaging of Lethal Prostate Cancer.

Clin Cancer Res 2020 03 15;26(5):1054-1064. Epub 2019 Nov 15.

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota.

Purpose: Aggressive variant prostate cancer (AVPC) is a nonandrogen receptor-driven form of disease that arises in men in whom standard-of-care therapies have failed. Therapeutic options for AVPC are limited, and the development of novel therapeutics is significantly hindered by the inability to accurately quantify patient response to therapy by imaging. Imaging modalities that accurately and sensitively detect the bone and visceral metastases associated with AVPC do not exist.

Experimental Design: This study investigated the transmembrane protein CD133 as a targetable cell surface antigen in AVPC. We evaluated the expression of CD133 by microarray and IHC analysis. The imaging potential of the CD133-targeted IgG (HA10 IgG) was evaluated in preclinical prostate cancer models using two different imaging modalities: near-infrared and PET imaging.

Results: Evaluation of the patient data demonstrated that CD133 is overexpressed in a specific phenotype of AVPC that is androgen receptor indifferent and neuroendocrine differentiated. In addition, HA10 IgG was selective for CD133-expressing tumors in all preclinical imaging studies. PET imaging with [Zr]Zr-HA10 IgG revealed a mean %ID/g of 24.30 ± 3.19 in CD133-positive metastatic lesions as compared with 11.82 ± 0.57 in CD133-negative lesions after 72 hours ( = 0.0069). biodistribution showed similar trends as signals were increased by nearly 3-fold in CD133-positive tumors ( < 0.0001).

Conclusions: To our knowledge, this is the first study to define CD133 as a targetable marker of AVPC. Similarly, we have developed a novel imaging agent, which is selective for CD133-expressing tumors, resulting in a noninvasive PET imaging approach to more effectively detect and monitor AVPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056526PMC
March 2020

New insights in predictive determinants of the tumor immune microenvironment for immune checkpoint inhibition: a never ending story?

Ann Transl Med 2019 Jul;7(Suppl 3):S135

Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.

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http://dx.doi.org/10.21037/atm.2019.06.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685893PMC
July 2019

Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.

Clin Cancer Res 2020 03 16;26(6):1247-1257. Epub 2019 Sep 16.

University of Alabama, Birmingham, Alabama.

Purpose: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137).

Patients And Methods: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability.

Results: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses.

Conclusions: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528620PMC
March 2020

Genomic Analysis and Treatment Response of a Bladder Urothelial Carcinoma With Sarcomatoid Variant Histology.

Clin Genitourin Cancer 2019 10 25;17(5):e888-e892. Epub 2019 May 25.

Department of Urology, University of Minnesota, Minneapolis, MN.

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http://dx.doi.org/10.1016/j.clgc.2019.05.019DOI Listing
October 2019

A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors.

Oncologist 2019 09 6;24(9):1151-e817. Epub 2019 Jun 6.

Cleveland Clinic, Cleveland, Ohio, USA.

Lessons Learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape.

Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC.

Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed.

Results: No patients in the dose-escalation phase ( = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached).

Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.
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http://dx.doi.org/10.1634/theoncologist.2018-0749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738313PMC
September 2019

Germline Genetic Testing in Advanced Prostate Cancer; Practices and Barriers: Survey Results from the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium.

Clin Genitourin Cancer 2019 08 18;17(4):275-282.e1. Epub 2019 Apr 18.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA. Electronic address:

Background: Germline genetic testing increasingly identifies advanced prostate cancer (PCa) patients who are candidates for precision therapies. The Prostate Cancer Clinical Trials Consortium (PCCTC) established the Germline Genetics Working Group to provide guidance and resources to expand effective use of germline genetic testing.

Materials And Methods: A 14-item questionnaire was e-mailed to academic oncologists at 43 PCCTC sites to collect information on germline genetic testing patterns, including patients considered, choice of assays, barriers slowing adoption, and actions to overcome barriers.

Results: Twenty-six genitourinary oncologists from 19 institutions responded. Less than 40% (10 of 26) reported referring patients to a genetics department, whereas the remainder take personal responsibility for genetic testing and counseling; 16 (62%) consider testing all metastatic PCa patients, whereas 3 (12%) consider testing all patients with high-risk local disease; and 7 (27%) use multigene comprehensive pan-cancer panels, and 14 (54%) use smaller or targeted cancer gene panels. Barriers to widespread use are: (1) delayed or limited access to genetic counseling; (2) no insurance coverage; (3) lack of effective workflows; (4) insufficient educational materials; and (5) time and space constraints in busy clinics. The primary limitation was the <50% (19 of 43) response from PCCTC sites and no coverage of nonacademic cancer treatment facilities.

Conclusion: Joint efforts by urologists, oncologists, genetics counselors, insurers, and cancer centers can accelerate implementation of integrated germline genetic services for personalized treatment and clinical trial eligibility for PCa patients.
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http://dx.doi.org/10.1016/j.clgc.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662206PMC
August 2019

Correction to: Immunotherapy Advances in Urothelial Carcinoma.

Curr Treat Options Oncol 2019 May 23;20(7):53. Epub 2019 May 23.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

In the original version of this article, which published in Current Treatment Options in Oncology, Volume 20, Issue 12, December 2018, the surname of the third author was captured incorrectly. The name shown above is correct.
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http://dx.doi.org/10.1007/s11864-019-0660-3DOI Listing
May 2019