Tumor microenvironment as a therapeutic target in cancer

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.

/pdf/complex-roles-of-the-stroma-in-the-intrinsic-resistance-to-4cayg16uui.pdf

Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going.

Progress in the knowledge and treatment of advanced pancreatic cancer: From benchside to bedside

Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer

Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4-9.7) and 10.1 months (95 % CI: 3.6-20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer.

Background The pancreatic tumor microenvironment is rich in receptors for platelet-derived growth factor (PDGFRs). Imatinib mesylate (IM) inhibits PDGFRs and decreases tumor interstitial fluid pressure, potentially improving drug access. These data and promising results in a phase 1 trial formed the rationale for a phase 2 trial combining IM and gemcitabine (GEM) in pancreatic cancer. Methods Eligibility criteria included chemotherapy-naive, locally advanced or metastatic pancreatic cancer; ECOG (Eastern Cooperative Oncology Group) performance status ≤2; and adequate end-organ function. The primary end point was progression-free survival (PFS). Secondary end points included response rate, toxicity, and overall survival (OS). GEM was given at 1200 mg/m(2)/120 min on days 3 and 10. IM (400 mg) was taken orally on days 1 to 5 and 8 to 12 of a 21-day cycle. Response was assessed every 3 cycles. Results Forty-four patients from 7 centers were enrolled from October 2005 through July 2009. Median age was 62 years. The median number of cycles completed was 3 (range, 0-17). Common adverse effects included neutropenia, nausea, anemia, and fatigue. Half the patients required dose reductions. There were no complete responses to therapy. During treatment, 1 patient showed a partial response, 16 had stable disease, and 18 had progressive disease. The median PFS was 3.9 months (95% confidence interval, 2.1-5.1), the median OS was 6.3 months (95% confidence interval, 5.2-8.5), and the 1-year survival rate was 25.6% (95% confidence interval, 13.8-39.1). Conclusion IM in combination with GEM is tolerated in locally advanced, metastatic, or recurrent pancreatic cancer, but does not show a statistically significant PFS or OS benefit over chemotherapy with GEM alone.

A Multi-institutional Phase 2 Study of Imatinib Mesylate and Gemcitabine for First-Line Treatment of Advanced Pancreatic Cancer.

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A Multi-institutional Phase 2 Study of Imatinib Mesylate and Gemcitabine for First-Line Treatment of Advanced Pancreatic Cancer.