Targeting apoptotic pathways for cancer therapy.

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.

A Somatic BRCA2-Mutated Pancreatic Adenocarcinoma With Sustained Exceptional Response to Modified FOLFIRINOX.

Homologous recombination repair (HRR) pathway deficiency opens multiple therapeutic avenues within pancreatic cancer. Patients with HRR deficiency-associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cancer, as well as the challenges associated with treatment and prevention of central nervous system metastases in long-term survivors of pancreatic cancer.

Chemotherapy and Immune Checkpoint Blockade for Gastric and Gastroesophageal Junction Adenocarcinoma.

Importance: Combining immune checkpoint blockade (ICB) with chemotherapy improves outcomes in patients with metastatic gastric and gastroesophageal junction (G/GEJ) adenocarcinoma; however, whether this combination has activity in the perioperative setting remains unknown. Objective: To evaluate the safety and preliminary activity of perioperative chemotherapy and ICB followed by maintenance ICB in resectable G/GEJ adenocarcinoma. Design, Setting, and Participants: This investigator-initiated, multicenter, open-label, single-stage, phase 2 nonrandomized controlled trial screened 49 patients and enrolled 36 patients with resectable G/GEJ adenocarcinoma from February 10, 2017, to June 17, 2021, with a median (range) follow-up of 35.2 (17.4-73.0) months. Thirty-four patients were deemed evaluable for efficacy analysis, with 28 (82.4%) undergoing curative resection. This study was performed at 4 referral institutions in the US. Interventions: Patients received 3 cycles of capecitabine, 625 mg/m2, orally twice daily for 21 days; oxaliplatin, 130 mg/m2, intravenously and pembrolizumab, 200 mg, intravenously with optional epirubicin, 50 mg/m2, every 3 weeks before and after surgery with an additional cycle of pembrolizumab before surgery. Patients received 14 additional doses of maintenance pembrolizumab. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR) rate. Secondary end points included overall response rate, disease-free survival (DFS), overall survival (OS), and safety. Results: A total of 34 patients (median [range] age, 65.5 [25-90] years; 23 [67.6%] male) were evaluable for efficacy. Of these patients, 28 (82.4%) underwent curative resection, 7 (20.6%; 95% CI, 10.1%-100%) achieved pCR, and 6 (17.6%) achieved a pathologic near-complete response. Of the 28 patients who underwent resection, 4 (14.3%) experienced disease recurrence. The median DFS and OS were not reached. The 2-year DFS was 67.8% (95% CI, 0.53%-0.87%) and the OS was 80.6% (95% CI, 0.68%-0.96%). Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 20 patients (57.1%), and 12 (34.3%) experienced immune-related grade 3 or higher adverse events. Conclusion and Relevance: In this trial of unselected patients with resectable G/GEJ adenocarcinoma, capecitabine, oxaliplatin, and pembrolizumab resulted in a pCR rate of 20.6% and was well tolerated. This trial met its primary end point and supports the development of checkpoint inhibition in combination with perioperative chemotherapy in locally advanced G/GEJ adenocarcinoma. Trial Registration: ClinicalTrials.gov Identifier: NCT02918162.

Smoking is Not Associated with Lung Metastasis in Pancreatic Cancer.

Smoking is a risk factor for pulmonary metastasis in various malignancies. We investigated this association for pancreatic ductal adenocarcinoma (PDAC). We conducted a retrospective 1:2 case-control study of consecutive patients who underwent PDAC resection (2011-2021). Cases ultimately developed lung metastases and controls did not. Of 744 patients we identified 53 cases and 106 matched controls. Twenty-five (47%) cases and 50 (47%) matched controls had a history of smoking (p = 1.0). This indicates that smoking is not associated with increased risk of pulmonary metastasis in resectable PDAC. Further research is needed to elucidate tumor and parenchymal factors influencing metastatic site.

Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer.

Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells.

Cytotoxic chemotherapy potentiates the immune response and efficacy of combination CXCR4/PD-1 inhibition in models of pancreatic ductal adenocarcinoma.

Purpose: The CXCL12-CXCR4 chemokine axis plays a significant role in modulating T-cell infiltration into the pancreatic tumor microenvironment. Despite promising preclinical findings, clinical trials combining inhibitors of CXCR4 (AMD3100/BL-8040) and anti-programmed death 1/ligand1 (anti-PD1/PD-L1) have failed to improve outcomes. Experimental Design: We utilized a novel ex vivo autologous patient-derived immune/organoid (PDIO) co-culture system using human peripheral blood mononuclear cells and patient derived tumor organoids, and in vivo the autochthonous LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) pancreatic cancer mouse model to interrogate the effects of either monotherapy or all combinations of gemcitabine, AMD3100, and anit-PD1 on CD8+ T cell activation and survival. Results: We demonstrate that disruption of the CXCL12-CXCR4 axis using AMD3100 leads to increased migration and activation of CD8+ T-cells. In addition, when combined with the cytotoxic chemotherapy gemcitabine, CXCR4 inhibition further potentiated CD8+ T-cell activation. We next tested the combination of gemcitabine, CXCR4 inhibition, and anti-PD1 in the KPC pancreatic cancer mouse model and demonstrate that this combination markedly impacted the tumor immune microenvironment by increasing infiltration of natural killer cells, the ratio of CD8+ to regulatory T-cells, and tumor cell death while decreasing tumor cell proliferation. Moreover, this combination extended survival in KPC mice. Conclusions: These findings suggest that combining gemcitabine with CXCR4 inhibiting agents and anti-PD1 therapy controls tumor growth by reducing immunosuppression and potentiating immune cell activation and therefore may represent a novel approach to treating pancreatic cancer.

Oral administration of TRAIL-inducing small molecule ONC201/TIC10 prevents intestinal polyposis in the Apc min/+ mouse model.

Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (n=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc min/+ male and female mice (n≥20) treated with colon carcinogen azoxymethane (AOM) (AOM-Apc min/+) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (P<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P<0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P<0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P<0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P<0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1ß, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM-Apc min/+ mouse model.

Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.

A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors.

PURPOSE: To evaluate the safety and tolerability in phase I first-in-human combination therapy with pexidartinib, an inhibitor of colony-stimulating factor-1 receptor, and sirolimus, an mTOR inhibitor, to target tumor-associated macrophage (TAM) polarization in soft tissue sarcomas (STS). PATIENTS AND METHODS: This multicenter phase I study used the time-to-event continual reassessment method (TITE-CRM) to study the combination of sirolimus, doses ranging from 2 to 6 mg, with pexidartinib, doses ranging from 600 to 1,000 mg, both provided continuously on a 28-day cycle, in patients with advanced sarcoma. A total of 24 patients [8 malignant peripheral nerve sheath tumor, 3 tenosynovial giant cell tumor (TGCT), 5 leiomyosarcoma, and 8 with other sarcoma subtypes] were enrolled. The median age was 46 years, 56% were male, and 61% had >2 prior lines of therapy. RESULTS: The recommended phase II dose was 2 mg of sirolimus combined with 1,000 mg of pexidartinib daily. Of the 18 evaluable subjects, 5 experienced dose-limiting toxicities (2 elevated aspartate aminotransferase/alanine aminotransferase, 2 elevated sirolimus trough levels, and 1 grade 5 dehydration). Most common grade 2 or higher treatment-related adverse events included anemia, fatigue, neutropenia, and lymphopenia. Clinical benefit was observed in 12 of 18 (67%) evaluable subjects with 3 partial responses (all in TGCT) and 9 stable disease. Tissue staining indicated a decreased proportion of activated M2 macrophages within tumor samples with treatment. CONCLUSIONS: Pexidartinib can be safely administered with sirolimus. These findings support further investigation of this combination to determine clinical efficacy. Clinicaltrials.gov identifier NCT02584647.

Advances in Systemic Therapy for Gastric Cancer.

Gastric cancer represents a major global health problem. Approximately half of patients are diagnosed with early stage disease and surgical resection is potentially curative. The addition of combination chemotherapy, with or without radiotherapy, to surgery has been shown to improve outcomes. In metastatic disease, combination chemotherapy in the form of 2- or 3-drug regimens has been used. The aim of this chapter is to summarize currently approved systemic treatment options for gastric cancer and to highlight several promising treatments currently under investigation.

Prolonged Response to HER2-Directed Therapy in Three Patients with HER2-Amplified Metastatic Carcinoma of the Biliary System: Case Study and Review of the Literature.

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2-targeting agents have been incorporated into the treatment paradigms for HER2-overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. This study discusses two patients with gallbladder carcinoma and a third with ampullary carcinoma who were able to achieve marked responses to HER2-directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2-directed therapy beyond breast and gastroesophageal cancers. KEY POINTS: Current guidelines recommend molecular assessment for HER2 overexpression exclusively in breast and gastric adenocarcinoma. The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 was detected and treatment with HER2-directed therapy resulted in robust responses. These cases exemplify responsiveness of non-breast/gastric histologies to HER2-directed therapies, highlighting several promising new settings for these agents. Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options.

Adjuvant FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Pancreatic Cancer: A Brown University Oncology Research Group Phase II Study (BrUOG295).

OBJECTIVES: Multiple clinical trials have established a role for adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Adjuvant FOLFIRINOX increases survival as compared with gemcitabine but with increased toxicity. FOLFOX+nab-paclitaxel (FOLFOX-A) was developed by the Brown University Oncology Research Group (BrUOG) as an alternative to FOLFIRINOX. This phase II trial explored the feasibility and toxicity of adjuvant FOLFOX-A in patients who have completed resection for pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: Patients with resected pancreatic ductal adenocarcinoma were eligible. The primary objective was to determine the feasibility of adjuvant FOLFOX-A. Patients experiencing grade 2 neuropathy received a 20% reduction of oxaliplatin. Secondary end points were disease-free survival, and overall survival. RESULTS: Between June 2014 and October 2018, 25 patients were enrolled following surgical resection. The median number of cycles completed was 9.5. Median disease-free survival was 19.7 months (95% confidence interval, 10.3 to not reached) and median overall survival was 53.5 months (95% confidence interval, 24.2 to not reached). The most common treatment-related grade 3 or greater adverse events were fatigue (58%), nausea (13%), and neutropenia (26%). Fourteen patients had grade 2 neuropathy (58%) and 1 patient (4%) had grade 3 neuropathy. Only 2 patients (8%) had grade 3 diarrhea. CONCLUSIONS: Adjuvant FOLFOX-A is a feasible multi-agent adjuvant treatment regimen and, with further validation, could be an alternative to FOLFIRINOX.

BRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease to treat. Despite advances in surgical techniques, radiation, and medical therapies, the 5-year survival rate remains below 9%. Over the past decade, the genomic landscape of PDAC has been well studied and BRCA mutations have emerged as a target for the development of more effective therapies. Alterations in germline BRCA and PALB2 are detected in approximately 5-9% of patients with PDAC and can lead to homologous repair deficiency (HRD). PDAC with HRD is more susceptible to cytotoxic agents, such as platinum salts and topoisomerase inhibitors, that cause DNA damage. Furthermore, PARP inhibitors have emerged as an effective non-cytotoxic approach to treating HRD-PDAC. In addition to BRCA and PALB2, germline mutations in other genes involved in the homologous DNA repair pathway - such as ATM and RAD51 - are potential targets, as are patients with the "BRCAness" phenotype and somatic mutations in the DNA repair pathway. Given the clinical implications of germline mutation related HRD in PDAC, universal germline testing is now recommended. In this review, we will discuss current and emerging biomarkers for HRD in PDAC, treatments, and the challenges associated with them.

Neoadjuvant Treatment for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options and exceedingly high mortality rates. Currently, cure can only be achieved through resection, however the vast majority of patients present with advanced disease for which upfront surgery is not an option. In an effort to improve surgical candidacy, neoadjuvant chemotherapy, with or without radiation therapy, is often used in an effort to downstage borderline resectable and locally advanced tumors, and some argue for its use even in patients with resectable tumors. Underlying this thinking is the recognition that pancreatic cancer is simultaneously both a locally invasive and systemic disease, even in patients without evidence of metastasis on imaging. Current evidence to date is largely retrospective, but suggests that neoadjuvant therapy can increase R0 (pathologically negative margin) resection rates and improve overall survival. The standard approach to neoadjuvant treatment involves choosing between the two most active combination regimens for metastatic disease, namely modified FOLFIRNOX and gemcitabine/nab-paclitaxel. Nonrandomized data indicate that these regimens can yield resection rates up to 68% and 36%, in borderline resectable and locally advanced PDAC, respectively. Furthermore, randomized data in patients with resectable PDAC treated with gemcitabine-based neoadjuvant therapy suggests that despite an approximate 10% drop in resection rates, there is a significant improvement in median overall survival. Herein, we will discuss the rationale for neoadjuvant therapy, current and former treatment regimens, common issues faced by clinicians when using these combinations, and several ongoing clinical trials.

Novel Agents in the Treatment of Relapsed or Refractory Peripheral T-Cell Lymphoma.

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell malignancies associated with exceptionally poor prognoses. Currently, chemotherapy remains the standard of care, but outcomes are suboptimal, with 5-year survival rates ranging from 15% to 25%. In recent years, several novel agents, including pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have been approved for the treatment of relapsed/refractory PTCL. In addition, numerous other therapies with different mechanisms of action and targets are currently under investigation. This article discusses in detail agents currently available, those currently under investigation, and active combination trials.

Atypical Hemolytic Uremic Syndrome Secondary to Lupus Nephritis, Responsive to Eculizumab.

Among the spectrum of disease manifestations associated with systemic lupus erythematosus, lupus nephritis is particularly concerning due to the potential for renal failure. This autoimmune attack may not, however, be limited to the kidney and is increasingly being recognized as a trigger for atypical Hemolytic Uremic Syndrome (aHUS). Atypical HUS falls under the spectrum of the thrombotic microangiopathies (TMAs) - a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage. Although plasma exchange is considered first-line therapy for thrombotic thrombocytopenic purpura - a TMA classically associated with autoimmune depletion of ADAMTS-13 - aHUS demonstrates less reliable responsiveness to this modality. Instead, use of the late complement inhibitor Eculizumab has emerged as an effective modality for the management of such patients. Diagnosis of aHUS, however, is largely clinically based, relying heavily upon a multidisciplinary approach. Herein we present the case of a patient with atypical HUS successfully treated with Eculizumab in the setting of Class IV-G (A) lupus nephritis and hypocomplementemia.

Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations.

Gastric and esophageal cancers represent a major global cancer burden and novel approaches are needed. Despite recent improvements in outcomes with trastuzumab and ramucirumab the prognosis for advanced disease remains poor, with a median overall survival of 1 year. Comprehensive genomic characterization has defined molecular subgroups and potentially actionable genomic alterations, but the majority of patients do not yet benefit from molecularly directed therapies. Breakthroughs in immune checkpoint blockade have provided new therapeutic avenues in melanoma, and continue to expand into other tumor types, with ongoing investigations in gastrointestinal (GI) malignancies. The frequency of programmed death ligand 1 (PD-L1) overexpression, a putative response biomarker, approaches forty percent in gastric cancers. Translational studies and molecular classification suggest gastric and esophageal cancers are candidate malignancies for immune checkpoint inhibition trials and early clinical data is promising. Here we review the mechanisms, preclinical, and early clinical data supporting the role for immune checkpoint blockade in gastric and esophageal cancer.