Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G 2 /M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

Objectives In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer. Methods Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion. Results The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination. Conclusions This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.

While well tolerated overall, this regimen demonstrated only modest antitumor activity in patients with metastatic pancreatic cancer. Recognizing the limits of cross-study comparisons and small sample size, these results do not match those reported at MTD in the phase I/II trial of gemcitabine/nab-paclitaxel. The lower doses used in the current study suggest that dose intensity may be a critical aspect to optimize multidrug regimens.

3105 Background: FOLFIRINOX has emerged as the optimal 1st-line treatment option for pts with advanced PDAC and good performance status; whether it can serve as the backbone upon which to add targeted agents in clinical trial design remains uncertain. The goal of this multicenter phase Ib study is to evaluate FOLFIRINOX in combination with saridegib, a novel oral agent that inhibits the Hh signaling pathway. In preclinical models of PDAC, saridegib increases chemotherapy delivery by depleting peritumoral stroma and increasing vascularity. Methods: Pts with previously untreated metastatic or locally advanced PDAC and ECOG PS 0-1 were eligible. Treatment consists of once-daily saridegib with concurrent administration of biweekly FOLFIRINOX (omitting the 5-FU bolus). A 3+3 dose escalation design was used (see dose levels below). Prophylactic WBC growth factor support is mandated.  DLT definitions include ALT/AST ≥10x ULN, grade 4 plts or ANC ≥5 d, or grade 3-4 nonheme toxicity. CT scans are obtained every 4 cycles. Limited PK analyses are performed. Results: Seven pts have been enrolled at the first 2 dose levels. Grade 1-2 AEs include GI (N/V/D), dehydration, fatigue, and LFT abnormalities. There was one DLT (grade 3 ALT elevation) at DL2. Other serious toxicities seen include grade 3 nausea (DL1) and grade 3 diarrhea (DL2). Tumor shrinkage has been observed in all 4 pts at DL1, ranging from 17-54%, with 2 unconfirmed PRs. Final MTD determination and updated safety and efficacy data will be presented at the meeting. Conclusions: A modified FOLFIRINOX regimen can be safely administered in combination with novel agents in clinical trials of PDAC. While saridegib was not beneficial when added to gemcitabine in a separate randomized phase II study, early evidence of significant responses on the current trial suggests that a more intensive chemotherapy platform may represent a preferable strategy in PDAC trial design. [Table: see text]