Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.

Purpose: A multicenter, randomized, open-label, phase II study (HERIZON; NCT02795988) was conducted to evaluate the clinical and immunologic efficacy of HER-Vaxx (IMU-131), a B-cell, peptide-based vaccine targeting HER2 overexpressed in 6% to 30% of gastroesophageal adenocarcinomas (GEA). Patients and Methods: Patients (n = 36) with GEA were treated with standard-of-care chemotherapy (n = 17) or HER-Vaxx plus chemotherapy (n = 19), using the recommended phase 2 dose for the vaccine. Overall survival (OS; primary endpoint), safety, progression-free survival (PFS), clinical response (secondary endpoints), and vaccine-induced HER2-specific antibody levels in serum and correlation with tumor response rates (exploratory endpoints) were investigated. Results: A 40% OS benefit [HR, 0.60; median OS, 13.9 months; 80% confidence interval (CI), 7.52–14.32] for patients treated with HER-Vaxx plus chemotherapy compared with OS of 8.31 months (80% CI, 6.01–9.59) in patients that received chemotherapy alone. A 20% PFS difference was obtained for the vaccination arm (HR, 0.80; 80% CI, 0.47, 1.38). No additional toxicity due to HER-Vaxx was observed. The vaccine-induced high levels of HER2-specific total IgG and IgG1 antibodies (P < 0.001 vs. controls) that significantly correlated with tumor reduction (IgG, P = 0.001; IgG1, P = 0.016), had a significant capacity in inhibiting phosphorylation of the intracellular HER2-signaling pathways, mediated antibody-dependent cellular cytotoxicity, and decreased immunosuppressive FOXP3+ regulatory T cells. Conclusions: HER-Vaxx plus standard chemotherapy exhibits an excellent safety profile and improves OS. Furthermore, vaccine-induced immune response was significantly associated with reduced tumor size compared with standard-of-care chemotherapy. The presented vaccination approach may substitute for treatment with trastuzumab, upon unavailability or toxicity, based on further evidence of equivalent treatment efficacy.

Https://doi.org/10.18632/oncotarget.28701 Dinara Ryspayeva, Attila A. Seyhan, William J. MacDonald, Connor Purcell, Tyler J. Roady, Maryam Ghandali, Nataliia Verovkina, Wafik S. El-Deiry, Martin S....

Acquired resistance to molecularly targeted therapies remains a formidable challenge in the treatment of cancer, despite significant advancements over the last several decades. We critically evaluate the evolving landscape of resistance mechanisms to targeted cancer therapies, with a focus on the genetic, molecular, and environmental contributors across a variety of malignancies. Intrinsic mechanisms such as mutations, drug and drug target modifications, and, notably, the activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways are mechanisms different malignancies use to combat therapeutic effectiveness. Furthermore, extrinsic alterations to the tumor microenvironment contribute to therapeutic resistance. We highlight similarities and differences in mechanisms across a wide spectrum of cancers including hematologic malignancies, non-small cell lung cancer, gastrointestinal, breast, and prostate cancers, pancreatic, ovarian, endometrial, and intracranial gliomas. Emerging strategies to overcome resistance, including multi-targeted approaches, combination therapies, and exploitation of synthetic lethality, are all critically discussed. We advocate for a nuanced understanding of resistance mechanisms as a cornerstone for developing future therapeutic strategies, emphasizing the necessity for integrated approaches that encompass genomic insights and precision medicine to outpace the dynamic and complex nature of cancer evolution and therapy resistance.

1063 Background: Rintodestrant, a potent, oral selective estrogen receptor degrader, competitively binds and degrades the estrogen receptor (ER), thus blocking ER signaling in tumors resistant to other endocrine therapies (ET). Results from parts 1 and 2 dose-escalation/expansion indicate that once-daily (QD) rintodestrant has a favorable safety profile and antitumor activity in patients (pts) with heavily pretreated ER+/HER2– advanced breast cancer (ABC), including those with ESR1 variants (Aftimos et al. SABCS 2020 [PS12-04, PD8-07]). The optimal dose of rintodestrant was 800 mg. Here, we present part 3, combining rintodestrant with the CDK4/6 inhibitor palbociclib. Methods: This open-label study evaluated rintodestrant in pts with ER+/HER2– ABC after progression on ET (NCT03455270). Part 3 assessed rintodestrant 800 mg QD + palbociclib 125 mg QD for 21 days every 28 days. Key eligibility criteria included ≤1 line of chemotherapy and/or ≤1 line of ET in the advanced setting, with ≥6 months of ET in the advanced setting and/or ≥24 months in the adjuvant setting. Prior CDK4/6 inhibitor therapy was not allowed. Primary objectives included safety and efficacy. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included mutation profiling (cell-free DNA) at baseline and cycle 1 day 15. Results: Enrollment occurred Jul–Oct 2020. As of Dec 9, 2020, 40 pts were treated, with a median age of 58 years (35–76) and ECOG PS of 0 (70%) or 1 (30%); 20% had de novo stage 4 disease, 10% bone-only, and 68% visceral metastases. Median number of visceral sites was 1 (0–3): 30% of pts with lung and 40% with liver involvement. Median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%). Most recent ET was given in the adjuvant and metastatic settings in 28% and 73% of pts, respectively. Rintodestrant-related adverse events (AEs) were reported in 8% of pts—all nonserious and grade 2—and included nausea (3%), vomiting (3%), and neutropenia (3%). The most common (≥10%) treatment-related AEs (rintodestrant and/or palbociclib) were neutropenia (88%), leukopenia (45%), anemia (10%), and thrombocytopenia (10%); grade 3/4 neutropenia was 38%/15%, in line with the safety profile of palbociclib. No deaths or treatment discontinuations due to AEs were reported. At data cutoff (median treatment duration of 3 months [1.5–4.6]), 28 pts (70%) remained on study treatment, 2 (5%) had a confirmed partial response, and 27 (68%) had stable disease. Additional efficacy and pharmacodynamic data will be presented. Conclusions: Rintodestrant, as monotherapy or combined with palbociclib, continues to demonstrate an excellent safety/tolerability profile with promising antitumor activity in pts with ER+/HER2– ABC, including those with ESR1 variants. Clinical trial information: NCT03455270 .

Background Conventionally, breast cancer (BC) prognosis and prediction of response to therapy are based on TNM staging, histological and molecular subtype, as well as genetic alterations. The role of various epigenetic factors has been elucidated in carcinogenesis. However, it is still unknown to what extent miRNAs affect the response to neoadjuvant chemotherapy (NACT). This pilot study is focused on evaluating the role of miR-34a, miR-124a, miR-155, miR-137 and miR-373 in response to NACT. Methods That was a prospective study enrolling 34 patients with histologically confirmed BC of II-III stages. The median age of patients was 53 (47–59.8) years old, 70.6% of whom were HR-positive. MiRs levels were measured in the primary tumor before and after NACT. The response to therapy was assessed after surgery using the Miller-Payne scoring system. To establish the role of miRs in modulating response to NACT the Cox model was applied for analysis. Results BC demonstrated a great variability of miRs expression before and after NACT with no strong links to tumor stage and molecular subtype. Only miR-124a and miR-373 demonstrated differential expression between malignant and normal breast tissues before and after therapy though these distinctions did not impact response to NACT. Besides miR-124a and miR-137 levels after NACT were found to be dependent on HR status. While miR-124a levels increased (p = 0.021) in the tumor tissue, the expression of miR-137 was downregulated (p = 0.041) after NACT in HR positive BC. Conclusions The study revealed differences in miR-124a and miR-373 expression after NACT in primary BC tissues. Although miRs levels did not impact the response to NACT, we found miR-124a and miR-137 levels to be related to hormonal sensitivity of BC.