Management of metastatic pancreatic cancer: Current treatment options and potential new therapeutic targets

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

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Androgenetic alopecia: combing the hair follicle signaling pathways for new therapeutic targets and more effective treatment options

Expert Opinion on Therapeutic Targets ◽

10.1080/14728222.2019.1659779 ◽

2019 ◽

Vol 23 (9) ◽

pp. 755-771 ◽

Cited By ~ 3

Author(s):

Alain P. Vasserot ◽

Mikhail Geyfman ◽

Neil J. Poloso

Keyword(s):

Effective Treatment ◽

Hair Follicle ◽

Signaling Pathways ◽

Treatment Options ◽

Therapeutic Targets ◽

Androgenetic Alopecia ◽

New Therapeutic Targets

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The mitochondrial metabolism inhibitor CPI-613 in combination with mFOLFIRINOX for pancreatic adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.264 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 264-264

Author(s):

Angela Tatiana Alistar ◽

Rodwige Desnoyer ◽

Ralph D'Agostino

Keyword(s):

Pancreatic Cancer ◽

Clinical Trial ◽

Phase I ◽

Response Rate ◽

Treatment Options ◽

Objective Response ◽

Stage Iv ◽

Phase I Clinical Trial ◽

Glutamine Metabolism ◽

Metastatic Pancreatic Cancer

264 Background: Stage IV pancreatic cancer is a lethal disease with limited treatment options. Current standard practice is combination chemotherapy with FOLFIRINOX or Gemcitabine + Abraxane. Despite these two new treatment options, the response rate and survival are limited in stage IV pancreatic cancer. The glycolic and mitochondrial metabolisms are aberrant in pancreatic cancer and translate into chemo-resistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as chemotherapy. CPI -613 is a novel anti-mitochondrial developed by Cornerstone Pharmaceuticals. Methods: A phase I clinical trial with mFOLFIRINOX+ CPI-613 in never treated for stage IV pancreatic cancer patients was initiated. The goals of this phase 1trial are: (1) To determine the Maximum Tolerated Dose (MTD) of CPI-613, when used in combination with mFOLFIRINOX, in patients with metastatic pancreatic cancer, (2) To assess the safety of CPI-613/ mFOLFIRINOX combination in patients with metastatic pancreatic cancer, and (3) To obtain preliminary data on efficacy of treatment with CPI-613/ mFOLFIRINOX Results: The MTD for CPI 613 was identified at 500mg/m2. The treatment combination is feasible and well-tolerated. The combination treatment was not found to have higher toxicity than FOLFIRINOX alone. The objective response rate was 53.9 % which is higher than FOLFIRINOX alone (reported as 31.6%). One patient has a complete radiologic and clinical response and two other patients have near complete responses. Conclusions: The preliminary efficacy data of this phase I clinical trial will inform a multi-institutional randomized phase II study of FOLFIRINOX vs. m FOLFIRINOX+ CPI613 in the near future. Clinical trial information: NCT01835041.

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Patterns of care in metastatic pancreatic cancer: patient selection in clinical routine

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819877635 ◽

2019 ◽

Vol 12 ◽

pp. 175628481987763 ◽

Cited By ~ 2

Author(s):

Werner Scheithauer ◽

Paul Martin Putora ◽

Birgit Grünberger ◽

Wolfgang Eisterer ◽

Ewald Wöll ◽

...

Keyword(s):

Pancreatic Cancer ◽

Decision Trees ◽

Patient Selection ◽

Performance Status ◽

Treatment Options ◽

Metastatic Pancreatic Cancer ◽

Decision Criteria ◽

First Line ◽

Clinical Routine ◽

Treatment Algorithms

Background: The management of patients with metastatic pancreatic cancer (mPC) is challenging, and the optimal treatment strategy is debated among experts. In an attempt to identify treatment decision criteria and to investigate variations in the first-line management of this disease, we performed an analysis of treatment algorithms among experts in the field of pancreatic cancer. The aim of this study was to identify relevant criteria in the complex process of patient selection and decision making for the management of mPC patients. Methods: Experts from the ABCSG (Austrian Breast and Colorectal Cancer Study Group) Pancreatic Cancer Club were contacted and agreed to participate in this analysis. Eight experts from seven centers in Austria provided their decision algorithms for the first-line treatment of patients with mPC. Their responses were converted into decision trees based on the objective consensus methodology. The decision trees were used to identify consensus and discrepancies. Results: The final treatment algorithms included four decision criteria (performance status, age, comorbidities, and symptomatic disease) and six treatment options: mFOLFIRINOX, gemcitabine + nab-paclitaxel, gemcitabine mono, 5-FU mono, gemcitabine/erlotinib, and best supportive care (BSC). Conclusions: We identified consensus for the treatment of young and fit patients with mFOLFIRINOX. With higher age and reduced performance status, gemcitabine + nab-paclitaxel was increasingly used. For patients with Eastern Co-operative Oncology Group Performance Status (ECOG PS) 4, BSC was the treatment of choice. Among experts, different decision criteria and treatment options are implemented in clinical routine. Despite multiple options in current recommendations, a consensus for specific recommendations was identified.

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Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death

Scientific Reports ◽

10.1038/s41598-019-53223-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Ligia I. Bastea ◽

Laeticia M. A. Hollant ◽

Heike R. Döppler ◽

Elizabeth M. Reid ◽

Peter Storz

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Cell Lines ◽

Apoptotic Cell ◽

Treatment Options ◽

Histone H3 ◽

Current Treatment ◽

Cancer Cell Death ◽

H3 Phosphorylation ◽

Histone H3 Phosphorylation

Abstract Current treatment options for patients with pancreatic cancer are suboptimal, resulting in a five year survival rate of about 9%. Difficulties with treatment are due to an immunosuppressive, fibrotic tumor microenvironment that prevents drugs from reaching tumor cells, but also to the limited efficacy of existing FDA-approved chemotherapeutic compounds. We here show that the nucleoside analog Sangivamycin and its closely-related compound Toyocamycin target PDA cell lines, and are significantly more efficient than Gemcitabine. Using KINOMEscan screening, we identified the kinase Haspin, which is overexpressed in PDA cell lines and human PDA samples, as a main target for both compounds. Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death. In orthotopically implanted tumors in mice, Sangivamycin was efficient in decreasing the growth of established tumors. In summary, we show that Sangivamycin and derivatives can be an efficient new option for treatment of PDA.

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New therapeutic targets in pancreatic cancer

Cancer Treatment Reviews ◽

10.1016/j.ctrv.2019.101926 ◽

2019 ◽

Vol 81 ◽

pp. 101926 ◽

Cited By ~ 19

Author(s):

Eleonora Lai ◽

Marco Puzzoni ◽

Pina Ziranu ◽

Andrea Pretta ◽

Valentino Impera ◽

...

Keyword(s):

Pancreatic Cancer ◽

Therapeutic Targets ◽

New Therapeutic Targets

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Novel 3D µtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics

Cancers ◽

10.3390/cancers13195006 ◽

2021 ◽

Vol 13 (19) ◽

pp. 5006

Author(s):

Kunal P. Pednekar ◽

Marcel A. Heinrich ◽

Joop van Baarlen ◽

Jai Prakash

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Treatment Options ◽

Treatment Strategies ◽

Collagen Gel ◽

Current Treatment ◽

Ductal Adenocarcinoma ◽

Tumor Type ◽

Cellular Interactions

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future.

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