Retrospective analysis of patients using olaparib (O) in pancreatic cancer (PC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 389-389
Author(s):  
Erkut Hasan Borazanci ◽  
Carol Guarnieri ◽  
Susan Haag ◽  
Ronald Lee Korn ◽  
Courtney Edwards Snyder ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Retrospective Analysis ◽  
Pearson Correlation ◽  
Brca2 Mutation ◽  
Dna Damage Repair ◽  
Parp Inhibitors ◽  
Damage Repair ◽  
Repair Deficiency

389 Background: Molecular analysis has revealed four subtypes of PC giving clinicians further insight into treating this deadly disease. One subtype that was elucidated termed “unstable” is significant for the presence of DNA damage repair deficiency and can be targeted therapeutically. One such therapy, O, from the drug class poly ADP ribose polymerase (PARP) inhibitors, has already been FDA approved for individuals with BRCA mutated ovarian cancers. We performed a retrospective analysis on patients with PC treated at a single institution who have DNA damage repair deficiency mutations and have been treated with O. Methods: A chart review identified pancreatic cancer patients with DNA repair pathway mutations who were treated with O. The primary objective examined ORR in patients with PC with DNA repair mutations receiving O. Secondary objectives included tolerability, overall survival (OS), CA 19-9 change, and changes in quantitative textural analysis (QTA) on CT. Results: 11 individuals were identified, 5 carriers of a pathogenic germline (g) BRCA2 mutation, 1 carrier of a pathogenic g ATM mutation, 1 carrier of a pathogenic g BRCA1 mutation. Variants of uncertain significance (VUS) included 1 g ATM mutation, 1 g PALB2 mutation, 1 somatic (s) C11orf30 mutation, and 1 s BRCA2 mutation. Median age at diagnosis was 59, with 4 M and 7 F. No patients met criteria for familial PC and 7 had a family history consistent for breast and ovarian cancer syndrome. All individuals had metastatic PC and had progressed on at least 1 line of systemic therapy. ORR was 18%. Median time of therapy on O was 5 months (mo) (Range 1.4 to 29.567 mo) with 5 of the individuals still undergoing treatment at the time of analysis. Mean OS was 12.35 mo, 9 of the 11 individuals still alive. QTA of baseline CTs from subjects with liver (8/11) and pancreatic tumors (7/11) revealed a strong association between lesion texture and OS (Pearson correlation coefficient (PCC): hepatic mets = 0.952, p = 0.0003) and time on O (PCC: panc lesions = 0.889, p = 0.006). Conclusions: In individuals with metastatic PC with mutations involved in DNA repair, O may provide clinical benefit. QTA of individual tumors may allow for additional information that predicts outcomes to PARP inhibitors in this population.

scholarly journals DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

Gut ◽  
2020 ◽  
pp. gutjnl-2019-319984 ◽  
Author(s):  
Lukas Perkhofer ◽  
Johann Gout ◽  
Elodie Roger ◽  
Fernando Kude de Almeida ◽  
Carolina Baptista Simões ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Dna Double Strand Breaks ◽  
Dismal Prognosis ◽  
Damage Repair ◽  
Personalised Treatment

Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.

scholarly journals The Potential of Using DNA Damage Repair Deficiency As a Biomarker for Cytarabine Response in AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2812-2812
Author(s):  
Clare Crean ◽  
Kienan I Savage ◽  
Ken I Mills
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cell Line ◽  
Cell Lines ◽  
Microarray Data ◽  
Radiation Treatment ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

Abstract Acute Myeloid Leukemia (AML) is most commonly seen in people over the age of 65 and has a median age of 63. Globally there is an increasingly elderly population so the rate of incidence of AML is set to increase. The therapy landscape for AML has changed little over the past four decades. Cytarabine, first approved in 1969, is still the standard of care induction therapy for AML. There has been only modest improvements in survival rates during this time and there is currently no method of determining which patients will or will not respond to Cytarabine treatment. An assay, developed in 2014, used microarray data to determine which breast cancer patients had a DNA Damage Repair Deficiency (DDRD) and therefore would be more susceptible to DNA damaging agents. A negative DDRD (DDRD-) score predicts that patients do not to have a DNA Repair Deficiency whilst patients with a positive DDRD (DDRD+) score are predicted to have a DNA Repair Deficiency. This assay has been adapted to different solid cancer types such as ovarian and oesophageal cancer. This project has assessed the potential of using the DDRD assay for AML patients. The assay was applied to publically available microarray data of >600 AML patients (TCGA AML data &GSE6891), who were classed as DDRD- or DDRD+. Excluding patients not treated with Cytarabine, this left 639 patients, 405 DDRD+ and 234 DDRD-. Kaplan Meier analysis showed the DDRD+ patients survived significantly (p=0.00047) worse than the DDRD- cohort. Whole exome sequencing was available for 183 patients (131 DDRD+) and the mutations associated with each group were identified. As the DDRD+ patients had the worst outcome, we focused on group. The list of genes more commonly mutated in the DDRD+ patients (>2 instances and >50% occurring in this group) were subjected to pathway analysis. Deregulated pathways included "leukemogenisis" and "cell proliferation and regulation"; however, the most deregulated pathway was "metabolism of nucleobase containing compounds". As Cytarabine is a nucleobase-containing compound, this is potentially a contributing factor as to why these patients responded poorly to this treatment. The assay was applied to microarray data of a panel of myeloid cell lines, and DDRD-(NB4 & SKM1) and a DDRD+(HL-60) cell line were chosen as experimental models. Clonogenic assays, used to analyse the effect of Cytarabine on these cell lines, showed that the DDRD- cell lines were more sensitive with a lower colony growth rate than the DDRD+cell line. DNA damage induction and repair, following cytarabine treatment or 2gy radiation, were measured using RAD51 foci counts. Whilst foci counts were high in all cell lines 2hrs and 4hrs following radiation, the DDRD+ cell line continued to show high levels after 24hrs whereas the levels in the DDRD- cell lines returned to a basal level. RAD51 response to radiation treatment showed that a repair defect is present in DDRD+ cells as they fail to repair the damage induced by radiation. Following treatment with Cytarabine however, few foci were seen in the DDRD+ cell line 2hrs, 4hrs or 24hrs following treatment whereas the DDRD- cell lines responded in a similar fashion to radiation treatment. That RAD51 foci are not present following Cytarabine treatment indicates that Cytarabine fails to induce damage in these cells. The DDRD assay has shown to be an effective method for determining cellular response to Cytarabine in vivo. The non-response of the DDRD+ cell line to Cytarabine suggests that these cells do not elicit a DNA damage or an apoptotic response. This perhaps contributes to their poorer outcome and suggests that Cytarabine is not an effective treatment plan for patients deemed to be DDRD+. Although alternative induction treatment options are currently unavailable for DDRD+ AML patients, this DDRD assay could be used as a biomarker for Cytarabine response in the future. Disclosures No relevant conflicts of interest to declare.

scholarly journals DNA damage repair deficiency as a predictive biomarker for FOLFIRINOX efficacy in metastatic pancreatic cancer

2019 ◽  
Vol 10 (6) ◽  
pp. 1133-1139 ◽  
Author(s):  
Sofia Palacio ◽  
Hannah S. McMurry ◽  
Robert Ali ◽  
Talia Donenberg ◽  
Rachel Silva-Smith ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Predictive Biomarker ◽  
Metastatic Pancreatic Cancer ◽  
Damage Repair ◽  
Repair Deficiency

scholarly journals Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics

2022 ◽  
Vol 9 ◽  
Author(s):  
Iain A. Richard ◽  
Joshua T. Burgess ◽  
Kenneth J. O’Byrne ◽  
Emma Bolderson
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Catalytic Domain ◽  
Current Knowledge ◽  
Dna Damage Repair ◽  
Cancer Therapeutics ◽  
Parp Inhibitors ◽  
Clinical Use ◽  
Cellular Functions ◽  
Damage Repair

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

scholarly journals MicroRNA-146a-5p enhances radiosensitivity in hepatocellular carcinoma through replication protein A3-induced activation of the DNA repair pathway

2019 ◽  
Vol 316 (3) ◽  
pp. C299-C311 ◽  
Author(s):  
Jing Luo ◽  
Zhong-Zhou Si ◽  
Ting Li ◽  
Jie-Qun Li ◽  
Zhong-Qiang Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Replication Protein ◽  
Repair Pathway ◽  
Related Factors ◽  
Damage Repair ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aimed to evaluate the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to replication protein A3 (RPA3). First, the limma package of R was performed to differentially analyze HCC expression chip, and regulative miRNA of RPA3 was predicted. Expression of miR-146a-5p, RPA3, and DNA damage repair pathway-related factors in tissues and cells was determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle, and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and the DNA repair pathway. The positive rate of ATM, pCHK2, and Rad51 in HCC tissues was higher when compared with that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3.

scholarly journals A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽  
2018 ◽  
Vol 60 (1) ◽  
pp. 39-47 ◽  
Author(s):  
Ashish P. Shah ◽  
Chhagan N. Patel ◽  
Dipen K. Sureja ◽  
Kirtan P. Sanghavi
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Repair Process ◽  
Parp Inhibitors ◽  
Brca Mutations ◽  
Development Of Resistance ◽  
Damage Repair ◽  
Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

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