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Complete metabolic response of metastatic castration-resistant neuroendocrine carcinoma of the prostate after treatment with RRx-001 and reintroduced platinum doublets.

ABSTRACT: Presented herein is the case of a heavily pretreated patient with high-grade neuroendocrine prostate cancer that achieved a complete metabolic response on platinum-based chemotherapy after treatment with the dual CD-47 and SIRP-? inhibitor, RRx-001, in a Phase II clinical trial.

SUBMITTER: Ojemuyiwa M

PROVIDER: S-EPMC6293266 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Complete metabolic response of metastatic castration-resistant neuroendocrine carcinoma of the prostate after treatment with RRx-001 and reintroduced platinum doublets.

Ojemuyiwa Michelle M Zeman Karen K Spira Alexander A Oronsky Bryan B Ray Carolyn C Trepel Jane B JB Lee Min-Jung MJ Onyiuke Ifeyinwa I Brzezniak Christina C

Clinical case reports 20181105 12

Presented herein is the case of a heavily pretreated patient with high-grade neuroendocrine prostate cancer that achieved a complete metabolic response on platinum-based chemotherapy after treatment with the dual CD-47 and SIRP-α inhibitor, RRx-001, in a Phase II clinical trial. ...[more]

PMID: 30564353

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Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization.

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Partial Response in an RRx-001-Primed Patient with Refractory Small-Cell Lung Cancer after a Third Introduction of Platinum Doublets.

Project description:Small-cell lung cancer (SCLC), initially exquisitely sensitive to first-line cisplatin/etoposide, invariably relapses and acquires a multidrug chemoresistant phenotype that generally renders retreatment with first-line therapy both futile and counterproductive. This report presents the case of a 77-year-old Caucasian male with extensive-stage refractory SCLC who was restarted on platinum doublets as part of a clinical trial called TRIPLE THREAT (NCT02489903) involving pretreatment with the epi-immunotherapeutic agent RRx-001, and who achieved a partial response after only 4 cycles. The patient had received a platinum drug twice before, in 2009 for a diagnosis of non-small-cell lung cancer (squamous cell carcinoma) and in 2015 for SCLC, suggesting that RRx-001 pretreatment may sensitize or resensitize refractory SCLC patients to first-line chemotherapy.

| S-EPMC4924447 | biostudies-literature

RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets.

Project description:RRx-001 is a pan-active, systemically nontoxic epigenetic inhibitor under investigation in advanced non-small cell lung cancer, small-cell lung cancer and high-grade neuroendocrine tumors in a Phase II clinical trial entitled TRIPLE THREAT (NCT02489903), which reexposes patients to previously effective but refractory platinum doublets after treatment with RRx-001. The purpose of this case study is first to report a partial response to carboplatin and etoposide in a patient with small-cell lung cancer pretreated with RRx-001, indicating episensitization or resensitization by epigenetic mechanisms, and second to discuss the literature related to small-cell lung cancer and episensitization.

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Project description:BackgroundThis exploratory single-arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small-cell lung cancer (SCLC).MethodsPatients were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by re-challenge with etoposide 80-100 IV mg/m2 on days 1, 2 and 3 and cisplatin 60-80 mg/m2 IV on day 1 or carboplatin AUC 5-6 IV on day 1, every 21 days. The primary end points were overall survival (OS) and overall response rate to platinum regimen.ResultsTwenty-six patients were enroled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1-9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, one patient (3.8%) had complete response and six (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrolment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse event from RRx-001 was mild discomfort at the infusion site (23%).ConclusionsRRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results.Clinical trial registrationNCT02489903.

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Project description:There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.Significance: Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. Cancer Res; 78(8); 2026-39. ©2018 AACR.

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Immune Reactivity and Pseudoprogression or Tumor Flare in a Serially Biopsied Neuroendocrine Patient Treated with the Epigenetic Agent RRx-001.

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Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors.

Project description:RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and in vivo T1 maps acquired 50 min (T150 min) after injection of 0.05 mmol/kg Gd-LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx-001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T150 min at 1 h post-drug was significantly longer than pre-drug tumor T150 min in all three tumor models, with the T150 min remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T150 min of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd-LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics.

| S-EPMC5731976 | biostudies-literature

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