The spectrum of cell death in sarcoma

The balance between cell death and cell survival is a highly coordinated process by which cells break down and remove unnecessary or harmful materials in a controlled, highly regulated, and compartmentalized manner. Cell exposure to various stresses, such as oxygen starvation, a lack of nutrients, or exposure to radiation, can initiate autophagy. Autophagy is a carefully orchestrated process with multiple steps, each regulated by specific genes and proteins. Autophagy proteins impact cellular maintenance and cell fate in response to stress, and targeting this process is one of the most promising methods of anti-tumor therapy. It is currently not fully understood how autophagy affects different types of tumor cells, which makes it challenging to predict outcomes when this process is manipulated. In this review, we will explore the mechanisms of autophagy and investigate it as a potential and promising therapeutic target for aggressive sarcomas

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer

Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective

Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model

Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence

Type I Cytokines Synergize with Oncogene Inhibition to Induce Tumor Growth Arrest

Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer but responses can be either short-lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAF(V600E)-mutant murine melanoma model (SB-3123), we explore potential mechanisms of synergy between the selective BRAF(V600E) inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8(+) T cells as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma-derived cell lines and was restricted to cancers bearing a BRAF(V600E)-mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the anti-proliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest have major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

IMPORTANCE: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. OBJECTIVE: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. INTERVENTIONS: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. MAIN OUTCOMES AND MEASURES: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. RESULTS: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P \u3c .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). CONCLUSIONS AND RELEVANCE: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00045968