Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.

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.

The Critical Need for a Meaning-Centered Team-Level Intervention to Address Healthcare Provider Distress Now.

COVID-19 has unveiled and amplified the burnout, grief, and other forms of distress among healthcare providers (HCPs) that long preceded the pandemic. The suffering of the healthcare workforce cannot be simply and sufficiently addressed with a single psychotherapeutic intervention. Nevertheless, the National Academies of Sciences, Engineering, and Medicine Studies recommended prioritizing interventions that generate an increased sense of meaning in life and in work to reduce burnout and cultivate clinician wellbeing. Despite their guidance, there is a dearth of interventions for HCPs specifically targeting meaning and purpose as an avenue to reduce HCP distress. In a time when such an intervention has never been more essential, Meaning-Centered Pyschotherapy (MCP), a brief, evidence-based intervention designed for patients with advanced cancer may be key. This piece describes the principles underlying MCP and how it might be adapted and applied to ameliorate burnout among HCPs while providing a rationale to support future empirical studies in this area. Importantly, the systemic factors that contribute to the emotional and mental health burdens of HCPs are discussed, emphasizing the need for systems-level changes that are needed to leverage the potential outcomes of MCP for HCPs.

A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma.

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.

A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer.

BACKGROUND: Substantial antitumor activity has previously been demonstrated with the addition of nab-paclitaxel (Abraxane [Celgene, Summit, NJ]), an albumin-bound formulation of paclitaxel, to gemcitabine in patients with advanced pancreatic cancer. Given preclinical evidence of synergy when a fluoropyrimidine is added to gemcitabine plus a taxane in a sequence-specific schedule, we conducted a phase I study to evaluate the combination of nab-paclitaxel, gemcitabine, and capecitabine administered biweekly in patients with metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with previously untreated metastatic pancreatic cancer and an ECOG performance status of 0-1 were eligible to participate. Study design utilized a 3 + 3 dose-escalation schema, with expanded cohort at maximum-tolerated dose (MTD). Treatment was administered in 14-day cycles, with capecitabine given on days 1-7 and both gemcitabine (at fixed-dose rate infusion) and nab-paclitaxel on day 4 of each cycle. Dose-limiting toxicity (DLT) definitions included grade 3-4 hematologic toxicities and grade 2-4 hand-foot syndrome, neuropathy, or diarrhea. RESULTS: Fifteen patients were enrolled across two dose levels. Final MTD was established at nab-paclitaxel 100 mg/m(2), gemcitabine 750 mg/m(2), and capecitabine 750 mg/m(2) twice daily. Patients received a median of four treatment cycles (range 1-16). The most frequent adverse events (any grade) for the entire study cohort included fatigue, rash/hand-foot syndrome, nausea/vomiting, diarrhea, neuropathy, and elevated liver function tests. Ten patients (66.7 %) experienced at least one grade 3-4 adverse event. Grade 3-4 hematologic toxicities were uncommon. Two of 14 evaluable patients (14.3 %) exhibited a partial response, and 6 of 12 patients (50 %) with elevated CA19-9 at baseline had a ≥50 % biomarker decline. CONCLUSION: 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.