RDH10 and ATRA sensitize triple-negative breast cancer to taxane-based chemotherapy through regulation of PIN1

Background: With few targeted therapies available for triple-negative breast cancer (TNBC), there is a critical need to identify biomarkers that can predict chemotherapy-response. Copy number amplifications (CNAmps) have been implicated in tumorigenesis, progression, and treatment response. Previously, we performed a prospective neoadjuvant chemotherapy study (BEAUTY) and identified a 5 Mb CNAmp in TNBC patients associated with pathological complete response rates to taxane- and anthracycline-based chemotherapy. Here we further interrogated this amplicon and its role in chemotherapy response. Methods: Using siRNA screening of genes identified in the 5 Mb CNAmp, followed by cytotoxicity assays, we identified RDH10 significantly associated with chemo-sensitivity in TNBC cell lines. Functional studies were performed using RDH10 knockdown or overexpression followed by cytotoxicity, cell proliferation, luciferase reporter assays, HPLC or western blot. Results: RDH10 is a rate-limiting step involved in the synthesis of all-trans retinoic acid (ATRA) - the active metabolite of retinoid metabolism that is frequently aberrant in cancer. Previous studies demonstrated ATRA to be a potent inhibitor of PIN1, a key regulator of several oncogenic signaling pathways often amplified in TNBC. We discovered that genetic manipulation of RDH10 affected ATRA intracellular concentrations, contributing to PIN1 degradation and taxane-response. Furthermore, co-treatment of TNBC cells with ATRA significantly increased taxane-sensitivity. Conclusion: RDH10 amplification increases endogenous levels of ATRA and degrades PIN1 in TNBC. ATRA-mediated degradation of PIN1 sensitizes TNBC to chemotherapy, suggesting that RDH10 may be a novel biomarker of taxane response and the addition of ATRA to standard chemotherapy may improve chemo-sensitivity.

RDH10 and ATRA sensitize triple-negative breast cancer to taxane-based chemotherapy through regulation of PIN1

Background: With few targeted therapies available for triple-negative breast cancer (TNBC), there is a critical need to identify biomarkers that can predict chemotherapy-response. Copy number amplifications (CNAmps) have been implicated in tumorigenesis, progression, and treatment response. Previously, we performed a prospective neoadjuvant chemotherapy study (BEAUTY) and identified a 5 Mb CNAmp in TNBC patients associated with pathological complete response rates to taxane- and anthracycline-based chemotherapy. Here we further interrogated this amplicon and its role in chemotherapy response. Methods: Using siRNA screening of genes identified in the 5 Mb CNAmp, followed by cytotoxicity assays, we identified RDH10 significantly associated with chemo-sensitivity in TNBC cell lines. Functional studies were performed using RDH10 knockdown or overexpression followed by cytotoxicity, cell proliferation, luciferase reporter assays, HPLC or western blot.Results: RDH10 is a rate-limiting step involved in the synthesis of all-trans retinoic acid (ATRA) - the active metabolite of retinoid metabolism that is frequently aberrant in cancer. Previous studies demonstrated ATRA to be a potent inhibitor of PIN1, a key regulator of several oncogenic signaling pathways often amplified in TNBC. We discovered that genetic manipulation of RDH10 affected ATRA intracellular concentrations, contributing to PIN1 degradation and taxane-response. Furthermore, co-treatment of TNBC cells with ATRA significantly increased taxane-sensitivity.Conclusion: RDH10 amplification increases endogenous levels of ATRA and degrades PIN1 in TNBC. ATRA-mediated degradation of PIN1 sensitizes TNBC to chemotherapy, suggesting that RDH10 may be a novel biomarker of taxane response and the addition of ATRA to standard chemotherapy may improve chemo-sensitivity.

Phase II study of pembrolizumab plus olaparib in the treatment of patients with advanced cholangiocarcinoma.

TPS4659 Background: Lack of an effective second-line treatment of patients (pts) with advanced cholangiocarcinoma (CC) necessitates the development of new therapies. Preclinical studies suggest CC susceptibility to PARP inhibition (PARPi): ERCC1 is underexpressed in 74% of CCs, and olaparib is selective for ERCC1 deficiency, profoundly inhibiting DNA repair. Additionally, PARPi exploits IDH mutation-related DNA damage repair deficiency, which is found in about 25% of CCs. Unfortunately, PARPi also upregulates PD-1-PD-L1 receptor-ligand binding, which attenuates anticancer immunity and counteracts the efficacy of PARPi. However, this can be prevented by PD-1 inhibition—blockade of PD-1-PD-L1 acts to re-sensitize cancer cells to T-cell killing. Hence, we hypothesize that the combination of olaparib and pembrolizumab will produce a durable anti-tumor response against CC by synergistically inducing DNA damage and increasing immune response. Methods: Thirty-six pts with advanced CC, who either failed to respond to or progressed on first-line therapy, will be enrolled to receive olaparib (300 mg PO bid) daily plus pembrolizumab (200 mg IV Q3 weeks) for 12 months, unless unacceptable toxicities or cancer progression occur, in which cases therapy will cease. MRI or CT tumor assessment will occur just before therapy, every 6 weeks for the first 6 months of therapy, and then every 9 weeks for the next 6 months of therapy (total, 12 months). Three tumor biopsies will be collected: at baseline; at week 4; and at time of progression. In each biopsy, ERCC1, PD-1, and PD-L1 expression, IDH1/2 mutation status, and immune cell (CD3 and CD8) response will be assessed. The total study duration will be 20-36 months. The primary endpoint will be overall response rate; the secondary endpoints will be PFS, OS, duration of response, and safety and tolerability. It is hypothesized that in pts with advanced CC, second-line therapy with olaparib plus pembrolizumab will improve the response rate from 17.5% to 35%, as well as increase PFS and OS compared to cytotoxic chemotherapy. Study enrollment began in Q1 2020. NCI number pending at time of abstract submission. Clinical trial information: pending at time of submission .

Post-Chemotherapy Titer Status and Need for Revaccination After Treatment for Childhood Cancer

Objectives. To evaluate the strategy of checking vaccine titers after completion of chemotherapy. Study Design. Retrospective review of pediatric oncology patients who completed chemotherapy. Demographics, post-chemotherapy titers, and absolute lymphocyte counts (ALCs) were analyzed. Results. Ninety patients met inclusion criteria, and 87% of patients had at least one titer checked. Comparing patients <7 years and those ≥7 years at diagnosis, there was no difference in incidence of negative titers except mumps; those <7 years old were more likely to have negative titers (58% vs 20%, P = .003). Comparing those <13 years old to ≥13 years old, there was no difference in negative titers except mumps (45% vs 19%, P = .02) and tetanus (44% vs 0%, P = .002). No patient maintained all protective titers after completion of chemotherapy. Time to ALC recovery was not predictive of positive titers. Conclusion. Checking titers after chemotherapy is not recommended. Providers should assume loss of immunity.

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING;

Background: Ginger has long been used as an antiemetic herb in various systems for traditional medicine. However, lack of data on its utility in preventing chemotherapy induced vomiting prevents us from reaching any definite statement. Objectives: To determine the effect of prophylactic use of ginger in decreasing the delayed chemotherapy induced vomiting, when added as an add on therapy to the standard antiemetic treatment in patients receiving highly emetogenic chemotherapy. Study Design: Randomized control trial. Setting: Department of Medical Oncology, Jinnah Hospital Lahore. Period: July 2014 and January 2016. Materials and Methods: A total of 90 patients were selected and randomly allocated into two groups, A and B, having 45 patients each. Patients in both groups received highly emetogenic chemotherapy regimens. For prophylaxis of CINV, Group A received olanzapine based standard antiemetic regimen and cap ginger 500 mg per oral TID 3 days prior to chemotherapy and 3 days after chemotherapy and Group B received olanzapine based standard antiemetic regimen only. Observation for frequency and grade of delayed chemotherapy induced vomiting in all cases was done at day 8 of chemotherapy. Results: The mean age of the patients in group A (intervention group) is 44.5±12.8 years and that in group B (standard group) is 41.4±13.9 years. 29 (64.4%) patients in the intervention group had no vomiting at all as compared to the 19(42.2%) patients in standard group. Mild/Grade 1 vomiting was experienced in 6 (13.3%) patients in the intervention group as compared to 9 (20.0%) patients in the standard arm. There was also a significant reduction in moderate/grade 2 vomiting in intervention arm 7 patients (15.5%) as compared to 11 patients ( 24.4%) in control arm. There was also significant reduction in the severe vomiting that is grade 3 and 4 in group A with the use of ginger capsulesas grade 3 vomiting was observed in only 6.6%versus 15.5% ptients, while none had grade 4 vomiting in group A compared to one patient (2.2%) in group B. Conclusion: Significant decrease in delayed chemotherapy induced vomiting was achieved in patients who were treated with standard antiemetic regimen plus ginger than those treated with standard antiemetic regimen alone, in patients receiving highly emetogenic chemotherapy. So the addition of ginger to standard antiemetic regimens is a safe, less expensive and effective additional treatment option.