Publications by authors named "Igor Astsaturov"

55 Publications

Identification of New Regulators of Pancreatic Cancer Cell Sensitivity to Oxaliplatin and Cisplatin.

Molecules 2022 Feb 14;27(4). Epub 2022 Feb 14.

"Biomarker" Research Laboratory, Institute of Fundamental Biology and Medicine, Kazan Federal University, 420008 Kazan, Russia.

The chemoresistance of tumor cells is one of the most urgent challenges in modern oncology and in pancreatic cancer, in which this problem is the most prominent. Therefore, the identification of new chemosensitizing co-targets may be a path toward increasing chemotherapy efficacy. In this work, we performed high-performance in vitro knockout CRISPR/Cas9 screening to find potential regulators of the sensitivity of pancreatic cancer. For this purpose, MIA PaCa-2 cells transduced with two sgRNA libraries ("cell cycle/nuclear proteins genes" and "genome-wide") were screened by oxaliplatin and cisplatin. In total, 173 candidate genes were identified as potential regulators of pancreatic cancer cell sensitivity to oxaliplatin and/or cisplatin; among these, 25 genes have previously been reported, while 148 genes were identified for the first time as potential platinum drug sensitivity regulators. We found seven candidate genes involved in pancreatic cancer cell sensitivity to both cisplatin and oxaliplatin. Gene ontology enrichment analysis reveals the enrichment of single-stranded DNA binding, damaged DNA binding pathways, and four associated with NADH dehydrogenase activity. Further investigation and validation of the obtained results by in vitro, in vivo, and bioinformatics approaches, as well as literature analysis, will help to identify novel pancreatic cancer platinum sensitivity regulators.
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http://dx.doi.org/10.3390/molecules27041289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875979PMC
February 2022

Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice.

PLoS One 2021 22;16(12):e0261633. Epub 2021 Dec 22.

Division of Hematology, Department of Medicine, Cardeza Center for Hemostasis, Thrombosis, and Vascular Biology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States of America.

We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls including at early stages, associated with reduced apoptosis in the tumors, in particular in tumor cells associated with platelet microvesicles-which were depleted of platelet-enriched miRNAs-demonstrating a specific role for platelet miRNAs in modulation of primary tumor growth. Differential expression RNA sequencing of tumor cells isolated from advanced primary tumors revealed a broad cohort of mRNAs modulated in the tumor cells as a function of host platelet miRNAs. Altered genes comprised 548 up-regulated transcripts and 43 down-regulated transcripts, mostly mRNAs altogether spanning a variety of growth signaling pathways-notably pathways related to epithelial-mesenchymal transition-in tumor cells from platelet miRNA-deleted mice compared with those from control mice. Tumors in platelet miRNA-depleted mice showed more sarcomatoid growth and more advanced tumor grade, indicating roles for host platelet miRNAs in tumor plasticity. We further validated increased protein expression of selected genes associated with increased cognate mRNAs in the tumors due to platelet miRNA depletion in the host animals, providing proof of principle of widespread effects of platelet miRNAs on tumor cell functional gene expression in primary tumors in vivo. Together, these data demonstrate that platelet-derived miRNAs modulate solid tumor growth in vivo by broad-spectrum restructuring of the tumor cell transcriptome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261633PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8694476PMC
January 2022

Preparation of mouse pancreatic tumor for single-cell RNA sequencing and analysis of the data.

STAR Protoc 2021 12 4;2(4):100989. Epub 2021 Dec 4.

The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Preparation of single-cell suspension from primary tumor tissue can provide a valuable resource for functional, genetic, proteomic, and tumor microenvironment studies. Here, we describe an effective protocol for mouse pancreatic tumor dissociation with further processing of tumor suspension for single-cell RNA sequencing analysis of cellular populations. We further provide an outline of the bioinformatics processing of the data and clustering of heterogeneous cellular populations comprising pancreatic tumors using Common Workflow Language (CWL) pipelines within user-friendly Scientific Data Analysis Platform (https://SciDAP.com). For complete details on the use and execution of this protocol, please refer to Gabitova-Cornell et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649395PMC
December 2021

Evaluating the impact of age on immune checkpoint therapy biomarkers.

Cell Rep 2021 08;36(8):109599

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins Bloomberg School of Medicine, Baltimore, MD, USA. Electronic address:

Both tumors and aging alter the immune landscape of tissues. These interactions may play an important role in tumor progression among elderly patients and may suggest considerations for patient care. We leverage large-scale genomic and clinical databases to perform comprehensive comparative analysis of molecular and cellular markers of immune checkpoint blockade (ICB) response with patient age. These analyses demonstrate that aging is associated with increased tumor mutational burden, increased expression and decreased promoter methylation of immune checkpoint genes, and increased interferon gamma signaling in older patients in many cancer types studied, all of which are expected to promote ICB efficacy. Concurrently, we observe age-related alterations that might be expected to reduce ICB efficacy, such as decreases in T cell receptor diversity. Altogether, these changes suggest the capacity for robust ICB response in many older patients, which may warrant large-scale prospective study on ICB therapies among patients of advanced age.
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http://dx.doi.org/10.1016/j.celrep.2021.109599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757482PMC
August 2021

Large-scale analysis of KMT2 mutations defines a distinctive molecular subset with treatment implication in gastric cancer.

Oncogene 2021 07 23;40(30):4894-4905. Epub 2021 Jun 23.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Frequent mutations of genes in the histone-lysine N-methyltransferase 2 (KMT2) family members were identified in gastric cancers (GCs). Understanding how gene mutations of KMT2 family affect cancer progression and tumor immune microenvironment may provide new treatment strategies. A total of 1245 GCs were analyzed using next-generation sequencing, whole transcriptome sequencing, immunohistochemistry (Caris Life Sciences, Phoenix, AZ). The overall mutation rate of genes in the KMT2 family was 10.6%. Compared to KMT2-wild-type GCs, genes involved in epigenetic modification, receptor tyrosine kinases/MAPK/PI3K, and DNA damage repair (DDR) pathways had higher mutation rates in KMT2-mutant GCs (p < 0.05). Significantly higher rates of high tumor mutational burden, microsatellite instability-high/mismatch-repair deficiency (dMMR), and PD-L1 positivity were observed in KMT2-mutant GCs (p < 0.01), compared to KMT2-wild-type GCs. The association between PD-L1 positivity and KMT2 mutations remained significant in the proficient-MMR and microsatellite stable subgroup. Based on transcriptome data from the TCGA, cell cycle, metabolism, and interferon-α/β response pathways were significantly upregulated in KMT2-mutant GCs than in KMT2-wild-type GCs. Patients with KMT2 mutation treated with immune checkpoint inhibitors had longer median overall survival compared to KMT2-wild-type patients with metastatic solid tumors (35 vs. 16 months, HR = 0.73, 95% CI: 0.62-0.87, p = 0.0003). In conclusion, this is the largest study to investigate the distinct molecular features between KMT2-mutant and KMT2-wild-type GCs to date. Our data indicate that GC patients with KMT2 mutations may benefit from ICIs and drugs targeting DDR, MAPK/PI3K, metabolism, and cell cycle pathways.
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http://dx.doi.org/10.1038/s41388-021-01840-3DOI Listing
July 2021

Feasibility of Fitness Tracker Usage to Assess Activity Level and Toxicities in Patients With Colorectal Cancer.

JCO Clin Cancer Inform 2021 01;5:125-133

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA.

Purpose: Performance status (PS) is a subjective assessment of patients' overall health. Quantification of physical activity using a wearable tracker (Fitbit Charge [FC]) may provide an objective measure of patient's overall PS and treatment tolerance.

Materials And Methods: Patients with colorectal cancer were prospectively enrolled into two cohorts (medical and surgical) and asked to wear FC for 4 days at baseline (start of new chemotherapy [± 4 weeks] or prior to curative resection) and follow-up (4 weeks [± 2 weeks] after initial assessment in medical and postoperative discharge in surgical cohort). Primary end point was feasibility, defined as 75% of patients wearing FC for at least 12 hours/d, 3 of 4 assigned days. Mean steps per day (SPD) were correlated with toxicities of interest (postoperative complication or ≥ grade 3 toxicity). A cutoff of 5,000 SPD was selected to compare outcomes.

Results: Eighty patients were accrued over 3 years with 55% males and a median age of 59.5 years. Feasibility end point was met with 68 patients (85%) wearing FC more than predefined duration and majority (91%) finding its use acceptable. The mean SPD count for patients with PS 0 was 6,313, and for those with PS 1, it was 2,925 (122 and 54 active minutes, respectively) ( = .0003). Occurrence of toxicity of interest was lower among patients with SPD > 5,000 (7 of 33, 21%) compared with those with SPD < 5,000 (14 of 43, 32%), although not significant ( = .31).

Conclusion: Assessment of physical activity with FC is feasible in patients with colorectal cancer and well-accepted. SPD may serve as an adjunct to PS assessment and a possible tool to help predict toxicities, regardless of type of therapy. Future studies incorporating FC can standardize patient assessment and help identify vulnerable population.
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http://dx.doi.org/10.1200/CCI.20.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189607PMC
January 2021

Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression.

Cancer Discov 2021 02 30;11(2):446-479. Epub 2020 Oct 30.

Cancer Biology Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1 cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1 CAFs are intrinsically immunosuppressive and inhibit natural killer cell-mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858242PMC
February 2021

Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer.

Cancer Cell 2020 10 24;38(4):567-583.e11. Epub 2020 Sep 24.

Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA; The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA; Kazan Federal University, Kazan, Russian Federation. Electronic address:

Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by Kras expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.
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http://dx.doi.org/10.1016/j.ccell.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572882PMC
October 2020

Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer.

Clin Cancer Res 2020 10 21;26(20):5348-5357. Epub 2020 Jul 21.

Massachusetts General Hospital, Boston, Massachusetts.

Purpose: The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).

Patients And Methods: Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.

Results: A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (95% CI, 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.

Conclusions: Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572624PMC
October 2020

A framework for advancing our understanding of cancer-associated fibroblasts.

Nat Rev Cancer 2020 03 24;20(3):174-186. Epub 2020 Jan 24.

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
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http://dx.doi.org/10.1038/s41568-019-0238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046529PMC
March 2020

Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma.

Clin Cancer Res 2018 03 6;24(6):1375-1388. Epub 2018 Feb 6.

Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.

The role of cholesterol biosynthesis in hedgehog pathway activity and progression of hedgehog pathway medulloblastoma (Hh-MB) were examined Statins, commonly used cholesterol-lowering agents, were utilized to validate cholesterol biosynthesis as a therapeutic target for Hh-MB. Bioinformatic analysis was performed to evaluate the association between cholesterol biosynthesis with hedgehog group medulloblastoma in human biospecimens. Alterations in hedgehog signaling were evaluated in medulloblastoma cells after inhibition of cholesterol biosynthesis. The progression of endogenous medulloblastoma in mice was examined after genetic blockage of cholesterol biosynthesis in tumor cells. Statins alone, or in combination with vismodegib (an FDA-approved Smoothened antagonist), were utilized to inhibit medulloblastoma growth Cholesterol biosynthesis was markedly enhanced in Hh-MB from both humans and mice. Inhibition of cholesterol biosynthesis dramatically decreased Hh pathway activity and reduced proliferation of medulloblastoma cells. Statins effectively inhibited medulloblastoma growth and functioned synergistically in combination with vismodegib. Cholesterol biosynthesis is required for Smoothened activity in the hedgehog pathway, and it is indispensable for the growth of Hh-MB. Targeting cholesterol biosynthesis represents a promising strategy for treatment of Hh-MB. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856627PMC
March 2018

Molecular characteristics of hepatocellular carcinomas from different age groups.

Oncotarget 2017 Nov 27;8(60):101591-101598. Epub 2017 Sep 27.

Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown, University, Washington, DC, USA.

While most patients in Western countries who are diagnosed with HCC are in their 50s and 60s, HCCs diagnosed at extremes of the age spectrum (i.e., < 40 years and ≥ 75 years) are less common and have been linked with distinct geographic locations and etiologies. Using multiplatform profiling, we identified differences in genetic alterations and protein expression in different age groups within a large cohort of HCC patients (N = 421). Young adult HCC patients (18-39 years' old) were more likely to be female, living in the West and Midwestern United States, and showed decreased androgen receptor, drug resistance and pro-angiogenic protein expression compared to older patients. mutations were the most frequent alteration in young adults (19%), whereas mutations occurred in 30-33% of patients ≥ 40 years' old. The overall frequency of pathogenic and presumed pathogenic mutations was observed to increase significantly with advancing age. To our knowledge, these data represent one of the only studies to analyze age-specific molecular profiles in HCC, and provide a basis for further exploration and validation of these findings with respect to their clinical and therapeutic implications.
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http://dx.doi.org/10.18632/oncotarget.21353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731898PMC
November 2017

Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP.

Oncotarget 2017 Oct 12;8(47):81776-81793. Epub 2017 Sep 12.

Department of Hematology/Oncology, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines (=16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including . We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs.
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http://dx.doi.org/10.18632/oncotarget.20819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669847PMC
October 2017

Future Clinical Trials: Genetically Driven Trials.

Authors:
Igor Astsaturov

Surg Oncol Clin N Am 2017 10 18;26(4):791-797. Epub 2017 Aug 18.

Department of Hematology and Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address:

The design of modern oncology clinical trials seeks to match patients' cancer molecular biomarkers with medications that specifically target those biomarkers, a general paradigm shift in cancer care coined clinical cancer biology. This approach exploits the synthetic lethality between a specific genetic alteration in the cancer cell and a drug: rapid termination of exaggerated kinase activity exemplifies this phenomenon. Synthetic lethality-based investigations are driven by rapidly evolving technologies for cancer molecular profiling. As these technologies evolve, future clinical trials will test drugs' activity based on the molecular mechanisms rather than by the tumor's appearance under a microscope.
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http://dx.doi.org/10.1016/j.soc.2017.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645064PMC
October 2017

Perspectives of HER2-targeting in gastric and esophageal cancer.

Expert Opin Investig Drugs 2017 May;26(5):531-540

c Program in Molecular Therapeutics and Department of Medical Oncology , Fox Chase Cancer Center , Philadelphia , PA , USA.

Introduction: The blockade of HER2 signaling has significantly improved the outlook for esophagogastric cancer patients. However, targeting HER2 still remains challenging due to complex biology of this receptor in gastric and esophageal cancers. Areas covered: Here, we review complex HER2 biology, current methods of HER2 testing and tumor heterogeneity of gastroesophageal cancer. Ongoing and completed clinical research data are discussed. Expert opinion: HER2 overexpression is a validated target in gastroesophageal cancer, with therapeutic implications resulting in prolonged survival when inhibited in the front-line setting. With standardized HER2 testing in gastro-esophageal cancer, the ongoing trials are testing newer agents and combinations including combination of anti-HER2 antibodies with immunotherapy. Clonal heterogeneity and emergence of resistance will challenge our approach to treating these patients beyond the frontline settings.
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http://dx.doi.org/10.1080/13543784.2017.1315406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563845PMC
May 2017

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.

Br J Cancer 2017 Apr 28;116(9):1203-1207. Epub 2017 Mar 28.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Background: Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.

Methods: We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.

Results: The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.

Conclusions: The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.
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http://dx.doi.org/10.1038/bjc.2017.77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418451PMC
April 2017

Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models.

Oncotarget 2017 Jan;8(3):4399-4409

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.

The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the "undruggable" KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008). STA-12-8666 also demonstrated dramatically superior activity in comparison to equimolar doses of irinotecan against 5 patient-derived pancreatic adenocarcinoma xenografts with prolonged remissions in some tumors. Analysis of activity of STA-12-8666 against tumor tissues and matched cell lines demonstrated prolonged accumulation and release of cytotoxic payload in the tumor leading to DNA damage response and cell cycle arrest.Our results provide a proof-of-principle validation that HSP90i-based drug conjugates can overcome the notorious treatment resistance by utilizing the inherently high affinity of pancreatic cancer cells to HSP90 antagonists.
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http://dx.doi.org/10.18632/oncotarget.12642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354841PMC
January 2017

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer.

Mol Cancer Ther 2016 10 9;15(10):2486-2497. Epub 2016 Aug 9.

Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Molecular and Cell Biology & Genetics Program, Drexel University College of Medicine, Philadelphia, Pennsylvania.

Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response-predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6-regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and pRB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC. Mol Cancer Ther; 15(10); 2486-97. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522587PMC
October 2016

Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study.

Br J Cancer 2016 08 2;115(5):564-70. Epub 2016 Aug 2.

Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA.

Background: The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical.

Methods: Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%).

Results: A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003).

Conclusions: Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.
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http://dx.doi.org/10.1038/bjc.2016.229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997552PMC
August 2016

The right and wrong of DOKing the nuclear receptor.

Authors:
Igor Astsaturov

EBioMedicine 2016 06 28;8. Epub 2016 May 28.

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.

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http://dx.doi.org/10.1016/j.ebiom.2016.05.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919501PMC
June 2016

Screening of Conditionally Reprogrammed Patient-Derived Carcinoma Cells Identifies ERCC3-MYC Interactions as a Target in Pancreatic Cancer.

Clin Cancer Res 2016 Dec 6;22(24):6153-6163. Epub 2016 Jul 6.

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients.

Experimental Design: We first developed a panel of new physiologic models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically.

Results: Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. The Cancer Genome Atlas analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors.

Conclusions: This provides initial preclinical evidence for an essential role of MYC-ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers. Clin Cancer Res; 22(24); 6153-63. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161635PMC
December 2016

Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection.

Am J Clin Oncol 2017 Aug;40(4):393-398

*Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY Departments of †Radiation Oncology §Medical Oncology ∥Pathology ††Surgical Oncology ¶Protocol Management Office, Fox Chase Cancer Center ‡Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA #Department of Surgical Oncology, Brigham and Women's Hospital, Boston, MA **Department of Medical Oncology, Yale University School of Medicine, New Haven, CT ‡‡Department of Biochemistry, Kazan Federal University, Kazan, Russia.

Objectives: Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates.

Methods: Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m/d over 96 h, weekly), paclitaxel (50 mg/m, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29).

Results: A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d.

Conclusions: Vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.
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http://dx.doi.org/10.1097/COC.0000000000000171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026539PMC
August 2017

Prognostic Significance of MUC-1 in Circulating Tumor Cells in Patients With Metastatic Pancreatic Adenocarcinoma.

Pancreas 2016 09;45(8):1131-5

From the *Department of Medical Oncology, †Protocol Support Laboratory, and ‡Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, PA; §South Jersey Regional Hospital, Vineland, NJ; ∥Clinical Trials Office, Fox Chase Cancer Center, Philadelphia, PA; and ¶Division of Hematology and Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH.

Objectives: Development of targeted therapies for pancreatic cancer could be enhanced by a reliable method for noninvasive tumor cell assessment. In this pilot study, we isolated and phenotypically characterized circulating tumor cells (CTCs) from patients with metastatic pancreatic cancer and explored their relationship to clinical outcome.

Methods: Peripheral blood from 50 patients was collected at treatment initiation and first disease evaluation for CTC enumeration and phenotyping by CellSearch® system. Expression of human mucin 1 (MUC-1) was performed.

Results: Forty-eight and 37 patients had evaluable samples at baseline and first disease evaluation, respectively. The cohort was 62% male, with a median age of 63 years. At least 1 CTC per 7.5 mL was detected in 23 patients (48%) pretreatment and 11 patients (30%) at first disease evaluation. No difference was seen in overall survival between patients with 1 or more CTCs versus no CTC at baseline (P = 0.14). Patients with MUC-1 expressing CTC (n = 10) had shorter median overall survival compared with those with MUC-1 negative CTC (n = 13; 2.7 vs 9.6 m; P = 0.044).

Conclusions: Circulating tumor cell enumeration and phenotypic characterization from metastatic pancreatic cancer patients are feasible. No correlation was found between CTC isolation and survival. However, the presence of MUC-1 expressing CTC demonstrated a trend toward inferior survival.
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http://dx.doi.org/10.1097/MPA.0000000000000619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983223PMC
September 2016

Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR.

Cell Rep 2015 Sep 3;12(11):1927-38. Epub 2015 Sep 3.

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420000, Russia. Electronic address:

Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRAS(G12D). Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling.
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http://dx.doi.org/10.1016/j.celrep.2015.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581991PMC
September 2015

HSP90 Inhibitor-SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors.

Mol Cancer Ther 2015 Nov 13;14(11):2422-32. Epub 2015 Aug 13.

Synta Pharmaceuticals Corp., Lexington, Massachusetts.

The clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor-drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0455DOI Listing
November 2015

Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer.

Ann Thorac Surg 2015 Jan 18;99(1):270-6. Epub 2014 Nov 18.

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Electronic address:

Background: The interval between neoadjuvant chemoradiation treatment and surgery has been described as an important predictor of pathologic response to therapy in nonesophageal cancer sites. We retrospectively reviewed our experience with patients who underwent neoadjuvant chemoradiation and esophagectomy to better understand the impact of the timing of surgery on pathologic complete response rates in esophageal cancer.

Methods: Two hundred thirty-one sequentially treated patients from 2000 to 2011 were identified for this study; 88 of these patients completed neoadjuvant chemoradiation followed by esophagectomy at our institution. The interval between completion of chemoradiation and surgery was calculated for each patient. The patients were categorized into quartiles and also into 3-week interval groups. Treatment factors and surgical morbidity data, including the estimated blood loss and length of operative stay, were also assessed.

Results: Quartiles for the neoadjuvant chemoradiation to surgery interval were less than 45 days, 46 to 50 days, 51 to 63 days, and 64+ days. Corresponding pathologic complete response rates were 12.5%, 20.0%, 22.7%, and 40.9% (p = 0.03). Results for 3-week intervals were similar (p = 0.02). There was no association between increasing time interval between the ending of neoadjuvant chemoradiation to surgery and length of stay longer than 2 weeks.

Conclusions: A longer interval between completion of neoadjuvant chemoradiation and surgery was associated with higher pathologic complete response rates without an impact on surgical morbidity.
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http://dx.doi.org/10.1016/j.athoracsur.2014.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284823PMC
January 2015

Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints.

Cell Cycle 2014 23;13(14):2172-91. Epub 2014 Jun 23.

Cancer Biology Program; Fox Chase Cancer Center; Philadelphia, PA USA.

Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as "authentic" bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents' gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient's tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers.
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http://dx.doi.org/10.4161/cc.29214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111673PMC
December 2015

Successful imatinib therapy for neuroendocrine carcinoma with activating Kit mutation: a case study.

J Natl Compr Canc Netw 2014 Jun;12(6):847-52

From the Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; Department of Medicine, Division of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York; and Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Neuroendocrine tumors (NET) and gastrointestinal stromal tumors (GIST) are believed to originate from the cells of Cajal that are randomly dispersed along the aerodigestive tract. Despite their distinct morphologic appearance, NET and GIST may share oncogenic mechanisms. Often presenting in the metastatic setting, treatment options for patients with NET are limited. This case report presents a patient with refractory metastatic NET that did not respond conventional chemotherapy. The patient was treated with a KIF11 inhibitor in a phase I clinical trial and experienced a prolonged and clinically meaningful partial response. On progression at 20 months, the patient's tumor was sequenced to reveal a KIT exon 11 mutation. Institution of imatinib therapy achieved a rapid and sustained antitumor effect with profound clinical benefit. Despite previously reported KIT expression in NET, this is the first documented case of an activating KIT mutation in NET and of successful treatment with both a KIF11 inhibitor and imatinib, each of which was elucidated through molecular profiling of the patient's tumor. Imatinib may be a valuable therapy in NET harboring activating KIT mutations.
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http://dx.doi.org/10.6004/jnccn.2014.0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112647PMC
June 2014

Molecular pathways: sterols and receptor signaling in cancer.

Clin Cancer Res 2014 Jan 24;20(1):28-34. Epub 2013 Oct 24.

Authors' Affiliations: Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania; Kazan Federal University, Republic of Tatarstan, Russia.

Accelerated cholesterol and lipid metabolism are the hallmarks of cancer and contribute to malignant transformation due to the obligatory requirement for cholesterol for the function of eukaryotic membranes. To build new membranes and maintain active signaling, cancer cells depend on high intensity of endogenous cholesterol biosynthesis and uptake of lipid particles. This metabolic dependency of cancer cells on cholesterol and other lipids is tightly regulated by the cholesterol homeostasis network, including (i) sterol response element-binding proteins (SREBP), master transcriptional regulators of cholesterol and fatty acid pathway genes; (ii) nuclear sterol receptors (liver X receptors, LXR), which coordinate growth with the availability of cholesterol; and (iii) lipid particle receptors, such as low-density lipid particle (LDL) receptor, providing exogenous sterol and lipids to cancer cells. In addition, activity of oncogenic receptors, such as MUC1 or EGFR, accelerates sterol uptake and biosynthesis. Therefore, a general strategy of reducing the cholesterol pool in cancer cells is challenged by the highly efficient feedback loops compensating for a blockade at a single point in the cholesterol homeostatic network. Besides the well-established structural role of cholesterol in membranes, recent studies have uncovered potent biologic activities of certain cholesterol metabolic precursors and its oxidized derivatives, oxysterols. The former, meiosis-activating sterols, exert effects on trafficking and signaling of oncogenic EGF receptor (EGFR). Cholesterol epoxides, the highly active products of cholesterol oxidation, are being neutralized by the distal sterol pathway enzymes, emopamyl-binding protein (EBP) and dehydrocholesterol-7 reductase (DHCR7). These recently discovered "moonlighting" activities of the cholesterol pathway genes and metabolites expand our understanding of the uniquely conserved roles these sterol molecules play in the regulation of cellular proliferation and in cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859141PMC
January 2014
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