DNA damage repair (DDR) pathway defects in gastrointestinal (GI) malignancies.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 647-647
Author(s):  
Ramya Thota ◽  
Gail Fulde ◽  
Mark Andrew Lewis ◽  
Derrick S. Haslem ◽  
Lincoln Nadauld ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Median Overall Survival ◽  
Parp Inhibitor ◽  
Stage Iv ◽  
Clinical History ◽  
Parp Inhibitors ◽  
Stage At Diagnosis ◽  
Damage Repair ◽  
Prostate Cancers ◽  
Generation Sequencing

647 Background: The clinical significance of the genomic alterations associated with DDR pathway in GI tumors (besides MMR defects) is largely unknown. These patients can potentially derive benefit from targeted therapy with poly ADP ribose polymerase (PARP) inhibitors, which have already shown promising activity in ovarian, breast and prostate cancers. In this study, we investigated the frequency and clinical significance of DDR repair defects (other than MMR defects) in GI tumors. Methods: We performed a retrospective analysis of all patients who had tumor next generation sequencing performed between January 2013 and August 2017 on GI cancers harboring DDR pathway defects. Data including demographics, clinical history, and treatment were extracted from patients' records. Results: Of 299 patients with GI tumors sequenced, 35 cases (12%) were noted to have DDR defects. The most commonly mutated genes – 6 (17%) BRCA2, 5 (14%) PALB2, 4 (11%) ATM, 3 (8.6%) BRCA1, 2 (5.7%) each of NBN, MUTYH, ERCC3, PARP1 amplification and 1 (2.8%) each of ERCC2, CDK12, and PARP2 amplification. Two patients had both ATM and BRCA2 mutations. Combination of ATM and MRE11, ATM and BRCA1, BRCA1 and ERCC6, BRCA2 and CDK12 were noted in 1 patient each. Of the 23 patients with available clinical data, the median age at diagnosis was 65 (range 30–85) years with male and female prevalence rates of 60.8% and 39.2%, respectively. Stage at diagnosis was I (n = 3), II (n = 3), III (n = 8), and IV (n = 9). The primary site of tumor was found in 8 (34.8%) colon, 4 (17.4%) liver, 4 (17.4%) pancreas, 2 (8.7%) esophagus, 2 (8.7%) anus, 2 (8.7%) appendix, 1 (4.3%) rectum. Seventeen patients received platinum‐based therapy, 7 were treated with PARP inhibitors and 5 patients received both platinum and PARP inhibitor. Median overall survival from diagnosis for patients with stage I/II was 65.3 months, stage III was 23.1 months, and stage IV was 22.4 months. The median survival of patients treated with olaparib was 24.5 months. Conclusions: DDR pathway defects in GI tumors are uncommon. However, they can potentially be targeted with PARP inhibitors with durable survival. Future clinical trials are warranted to explore the role to PARP inhibitors in these unique subset of patients.

scholarly journals Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Stephen Murata ◽  
Catherine Zhang ◽  
Nathan Finch ◽  
Kevin Zhang ◽  
Loredana Campo ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Parp Inhibitors ◽  
Damage Repair ◽  
Trial Testing ◽  
United States Food ◽  
States Food ◽  
And Personalized Medicine ◽  
Inhibitor Treatment

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use inBRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents inBRCAand non-BRCA-mutated cancers.

scholarly journals PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2054
Author(s):  
Elizabeth K. Lee ◽  
Ursula A. Matulonis
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Parp Inhibition ◽  
Combination Therapies ◽  
Mechanisms Of Resistance ◽  
Damage Repair ◽  
Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

EGFR amplification predicted selective sensitivity to PARP inhibitors with high PARP-DNA trapping potential in human GBM.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2047-2047
Author(s):  
W. K. Alfred Yung ◽  
Shaofang Wu ◽  
Feng Gao ◽  
Siyuan Zheng ◽  
Jie Ding ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibitors ◽  
Glioma Stem Cells ◽  
Egfr Amplification ◽  
Damage Repair ◽  
Selective Sensitivity ◽  
Dna Trapping

2047 Background: Poly-ADP-ribose polymerase (PARP) is an enzyme critical for regulating a variety of DNA damage repair mechanisms such as BER/SSBR, and PARP inhibitors have been shown to have single agent activity in breast and ovarian cancer patients with BRCA ½ mutations. However, PARP inhibitor such as veliparib has limited single agent activity in GBM and identifying markers predicting sensitivity is critical to select individuals or certain groups of patients for PARP inhibitor therapy. Methods: Potency and selectivity of PARP inhibitors were analyzed in a panel of glioma stem cells (GSCs) with varying genetic background. In vivo anti-tumor activity was evaluated in xenograft models. Results: In this study, we report that PARP inhibitor, talazoparib, showed strong single-agent cytotoxicity and remarkable selective activity in glioma stem cells (GSCs). This single agent activity was strongly correlated with EGFR amplification. GSCs with EGFR amplification (which occurs in about 45% of GBMs) showed higher oxidative base damage, DNA breaks, and genomic instability than non-amplified GSCs. To sustain the elevated basal oxidative stress, EGFR-amplified GSCs had increased basal expression of DNA repair proteins. As a result of blocked DNA damage repair by talazoparib treatment, DNA damage accumulated and lead to increased PARP-DNA complexes, which was then trapped by talazoparib and resulted in high toxicity. The PARP-DNA trapping function of PARPi is essential as olaparib and veliparib, two PARP inhibitors with weak DNA-PARP trapping potential did not show sensitivity in GSCs. In contrast, Pamiparib, another PARP inhibitor with similar PARP-DNA trapping ability to that of talazoparib, showed selective sensitivity in EGFR-amplified GSC. Conclusions: Our data showed that EGFR amplified GSCs with higher basal DNA damage exhibited therapeutic vulnerability to PARP inhibitors with high PARP-DNA trapping ability, and that EGFR amplification is a potential selection or predictive biomarker for PARP inhibitor therapy in GBM.

TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5005-5005 ◽  
Author(s):  
Joaquin Mateo ◽  
Nuria Porta ◽  
Ursula Brigid McGovern ◽  
Tony Elliott ◽  
Robert J Jones ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Response Rates ◽  
Damage Repair ◽  
Altered Gene ◽  
Prostate Cancers ◽  
Taxane Chemotherapy

5005 Background: We previously reported the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC (TOPARP-A; Mateo et al NEJM 2015). We now report TOPARP-B, a phase II trial for patients with mCRPC preselected for putatively pathogenic DDR alterations. Methods: Patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomized 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included progression-free survival (PFS), tolerability. Results: Overall, 98 patients (median age 67.6y) were randomized, with 92 patients treated and evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 37% (95%CI 23-53%) in the 300mg cohort. With a median follow-up of 17.6 months (mo), the overall median PFS (mPFS) was 5.4 mo. Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups. Conclusions: Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumors being most sensitive but with confirmed responses in patients with other DDR alterations. Clinical trial information: NCT01682772.

ABT-888 (veliparib) in combination with carboplatin in patients with stage IV BRCA-associated breast cancer. A California Cancer Consortium Trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1010-1010 ◽  
Author(s):  
George Somlo ◽  
Joseph A. Sparano ◽  
Tessa Cigler ◽  
Gini F. Fleming ◽  
Thehang H. Luu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Stage Iv ◽  
Parp Inhibitors ◽  
Maximum Tolerated Dose ◽  
Grade 3 ◽  
The Individual ◽  
Dose Levels ◽  
Better Than

1010 Background: Platinum and PARP inhibitors have both shown activity in BRCA-associated breast cancer (BC) patients (pts). We have conducted a phase I trial of carboplatin (Carb) and velapirib [V], a PARP inhibitor, to define dose limiting toxicities [(DLT) during cycle (C) 1] and the maximum tolerated dose (MTD). Methods: BRCA 1 or 2 carriers with stage IV BC were eligible. Carb starting at an AUC of 6 was given IV every 21 days (length of planned C) and V was administered orally, BID at dose levels (L) L1 through L5 (highest L planned). Results: 22 pts (21 eligible/evaluable, 20 with measurable BC) carrying BRCA1 (10) or BRCA2 (11), or both (1) mutations were accrued. Median age: 45 years, (32-65); 68% of BCs were ER+, and 10% were HER2+. In the table below are the schema, incidence of DLTs, and # of Cs on study. Toxicities: At L1, grade ¾ DLTs with C 1 were seen in 2/6 evaluable pts (1 pt w/grade 3 hyponatremia, pleural effusion, and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to deescalation of carb (AUC 5) for pts treated at Ls 2-5. At L2, 1 of 6 pts had grade 4 PLT. There were no DLTs at Ls 3 and L4. L5 is currently being expanded to 6 pts (3 currently enrolled, 1 pt with grade 4 granulocytopenia (Gr) and grade PLT reached DLT). Non-DLT dose delays mostly due ≥ grade 2 Gr or PLT were needed at 60%, 53%, 53%, and 43% of Cs in pts treated on Ls 1-4. Response: In 12 eligible pts treated at Ls 1 and 2, 2 complete and 6 partial responders (67%) and a clinical benefit (CB) of 75% were seen. All pts at Ls 3-5 are still being treated, and in pts treated at Ls 3 and 4, 2 unconfirmed PRs, and 4 cases of stable disease were seen, with L5 too early to assess. Conclusions: The combination of Carb at an AUC of 5 and daily V at doses 150 to 200 mg BID is feasible and the MTD is being defined. In preliminary analysis, response and CB rates are better than expected with the individual agents alone, providing justification to proceed with a planned phase II randomized single agent versus combination trial. [Table: see text]

Association of secondary somatic mutations in BRCA1/2 with clinical resistance to PARP inhibitors and chemotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1087-1087
Author(s):  
Lingjun Zhu ◽  
Yan Zhang ◽  
Pingping Dai ◽  
Ping Zhou ◽  
Hui Li ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Parp Inhibitor ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
The Other ◽  
Targeting Therapy ◽  
Platinum Based Chemotherapy ◽  
Clinical Resistance ◽  
Somatic Reversion ◽  
Generation Sequencing

1087 Background: Somatic reversion mutations in either BRCA1/2 has been reported to lead to the resistance of platinum-based chemotherapy or PARPi. In this study we try to analyze the secondary somatic mutations in BRCA1/2 in patients with germline mutations. Methods: Using gene-panel target-captore next generation sequencing, we analyzed the secondary somatic mutations from 86 patients with BRCA1/2 germline mutations. Results: Eighty-six cases with BRCA1/2 gremline mutations were identified. Secondary somatic mutations restoring BRCA1/2 were identified in 7 patients, including 2 breast cancer, 3 ovarian cancer, 1 prostate cancer and 1cholangiocarcinoma patient. For these seven patients, five had been treated with platinum-based chemotherapy without PARPi and the other two (patient 1 and 2) with PARPi (olaparib). Patient 1 and 2 both received targeting therapy of PARP inhibitor olaparib after the germline BRCA1/2 mutation was detected. About six months later, plasma ctDNA was sequenced. Result showed that the germline mutations remained and additional larger deletions was detected. These secondary somatic mutations are not predicted to significantly affect the BRCA1/2 protein, and are likely to cause resistance to platinum-based chemotherapy or PARPi therapy by restoring BRCA1/2 ORF and DNA repair function. Conclusions: Secondary somatic mutations that restore BRCA1/2 in carcinomas with germline BRCA1/2 mutations predict resistance to platinum-based chemotherapy and PARP inhibitors, some strategies to reverse this type of drug resistance need further investigation. [Table: see text]

Clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine tumors: A population-based analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21575-e21575
Author(s):  
Harry E Fuentes ◽  
Mojun Zhu ◽  
Jennifer Gile ◽  
Konstantinos Leventakos ◽  
Mohamad Bassam Sonbol ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Clinical Significance ◽  
Median Overall Survival ◽  
Stage Iv ◽  
Distant Metastases ◽  
Large Cell ◽  
Population Based ◽  
Histological Subtypes ◽  
Typical Carcinoid ◽  
Sizable Proportion

e21575 Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p < 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]

scholarly journals Epigenetic based synthetic lethal strategies in human cancers

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Aiai Gao ◽  
Mingzhou Guo
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Epigenetic Changes ◽  
Loss Of Function ◽  
Synthetic Lethal ◽  
Human Cancers ◽  
Damage Repair ◽  
Frequent Event ◽  
Cancer Types

Abstract Over the past decades, it is recognized that loss of DNA damage repair (DDR) pathways is an early and frequent event in tumorigenesis, occurring in 40-50% of many cancer types. The basis of synthetic lethality in cancer therapy is DDR deficient cancers dependent on backup DNA repair pathways. In cancer, the concept of synthetic lethality has been extended to pairs of genes, in which inactivation of one by deletion or mutation and pharmacological inhibition of the other leads to death of cancer cells whereas normal cells are spared the effect of the drug. The paradigm study is to induce cell death by inhibiting PARP in BRCA1/2 defective cells. Since the successful application of PARP inhibitor, a growing number of developed DDR inhibitors are ongoing in preclinical and clinical testing, including ATM, ATR, CHK1/2 and WEE1 inhibitors. Combination of PARP inhibitors and other DDR inhibitors, or combination of multiple components of the same pathway may have great potential synthetic lethality efficiency. As epigenetics joins Knudson’s two hit theory, silencing of DDR genes by aberrant epigenetic changes provide new opportunities for synthetic lethal therapy in cancer. Understanding the causative epigenetic changes of loss-of-function has led to the development of novel therapeutic agents in cancer. DDR and related genes were found frequently methylated in human cancers, including BRCA1/2, MGMT, WRN, MLH1, CHFR, P16 and APC. Both genetic and epigenetic alterations may serve as synthetic lethal therapeutic markers.

scholarly journals Case Report: Combination of Olaparib With Chemotherapy in a Patient With ATM-Deficient Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Georgios I. Papageorgiou ◽  
Evangelos Fergadis ◽  
Nikos Skouteris ◽  
Evridiki Christakos ◽  
Sergios A. Tsakatikas ◽  
...  
Keyword(s):  
Treatment Options ◽  
Stage Iv ◽  
Parp Inhibitors ◽  
Anti Cancer ◽  
Heavily Pretreated ◽  
Next Generation Sequencing Ngs ◽  
Other Neoplasms ◽  
Generation Sequencing ◽  
Current Report ◽  
Indications For Use

Poly-ADP ribose polymerase (PARP) inhibitors are constantly increasing in their indications for use as anti-cancer treatment in various neoplasms, the majority of which are linked with BRCA deficiency. Preclinical data support the investigation of PARP inhibitors in other neoplasms exhibiting “BRCAness” or homologous recombination deficiency (HRD) as monotherapy as well as in combination with chemotherapy. With the current report we present the case of a heavily pretreated 55-year-old male patient diagnosed with stage IV ATM-deficient CRC, who was effectively treated with an off-label olaparib-irinotecan combination after exhaustion of all available treatment choices; furthermore, we discuss the existing data providing evidence for the use of PARP inhibitors in ATM-deficient CRC and encourage the implementation of next-generation sequencing (NGS) in patients with no other available treatment options.

scholarly journals The role of PARP inhibitors in BRCA mutated pancreatic cancer

2021 ◽  
Vol 14 ◽  
pp. 175628482110148
Author(s):  
Jeffrey Chi ◽  
Su Yun Chung ◽  
Ruwan Parakrama ◽  
Fatima Fayyaz ◽  
Jyothi Jose ◽  
...  
Keyword(s):  
Dna Damage ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
The United States ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Tumor Cell Death ◽  
Brca Mutations ◽  
Damage Repair ◽  
The Us

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence relative to other solid tumors, it is one of the leading causes of cancer-related death in the US. PDAC is highly resistant to chemotherapy as well as radiation therapy. Current standard-of-care chemotherapeutic regimens provide transient disease control but eventually tumors develop chemoresistance. Tumors that are deficient in DNA damage repair mechanisms such as BRCA mutants respond better to platinum-based chemotherapies. However, these tumor cells can utilize the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) as a salvage DNA repair pathway to prolong survival. Hence, in the presence of BRCA mutations, the inhibition of the PARP pathway can lead to tumor cell death. This provides the rationale for using PARP inhibitors in patients with BRCA mutated PDAC. The phase III POLO trial showed a near doubling of progression-free survival (PFS) compared with placebo in advanced PDAC when a PARP inhibitor, olaparib, was used as maintenance therapy. As a result, the US Food and Drug Administration (FDA) approved olaparib as a maintenance treatment for germline BRCA mutated advanced PDAC that has not progressed on platinum-based chemotherapy. The success of olaparib in treating advanced PDAC opened the new field for utilizing PARP inhibitors in patients with DNA damage repair (DDR) gene defects. Currently, many clinical trials with various PARP inhibitors are ongoing either as monotherapy or in combination with other agents. In addition to germline/somatic BRCA mutations, some trials are enrolling patients with defects in other DDR genes such as ATM, PALB2, and CHEK2. With many ongoing PARP inhibitor trials, it is hopeful that the management of PDAC will continuously evolve and eventually lead to improved patient outcomes.

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