Abstract IA26: Dual functions of PARP1 in prostate cancer: mechanisms and implications for therapeutic intervention
Prostatic adenocarcinoma (PCa) is the 2nd leading cause of cancer death in US men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct AR antagonists, as PCa is exquisitely dependent on androgen receptor (AR) activity for survival. Furthermore, recent studies identified AR as a major effector of DNA repair, manifest through the ability of the receptor to regulate DNAPK expression and activity. While AR directed therapeutics effectively suppress the pro-proliferative, pro-survival, and p...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Knudsen, K. E. Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research
Abstract B26: Development of a proximity ligation assay for the detection of PARP-1 trapped to chromatin
Conclusion: The PLA trapping assay provides an improved methodology for evaluation of endogenous PARP-1 complexes bound to chromatin and may have utility for clinical tissue specimens where detection of PARP-1 trapping may lead to insights regarding efficacy and tolerability of PARP inhibitors.Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.Citation Format: Todd Hopkins, Barrett Ainsworth, Vivek Abraham, David Maag, Eric Johnson, Julie Wilsb...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hopkins, T., Ainsworth, B., Abraham, V., Maag, D., Johnson, E., Wilsbacher, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A26: High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway
Conclusion: We identified a subset of neuroblastoma tumors with a high CtoA mutation frequency, which correlates with losses of glycosylases involved in the repair of CtoA mutations. 8-Oxo-Guanine levels are elevated in cell lines with loss of OGG1 or MUTYH, which can be rescued by overexpression of OGG1 or MUTYH respectively.Citation Format: Anne Hakkert, Marli E. Ebus, Rogier Versteeg, Caron N. Huib, Jan Koster, Jan J. Molenaar. High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway [abstract]. In: Proceedings of the AACR Special Conference on ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hakkert, A., Ebus, M. E., Versteeg, R., Huib, C. N., Koster, J., Molenaar, J. J. Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA25: Novel mechanisms of PARP-inhibitor resistance in tumors with defects in the Fanconi Anemia/BRCA pathway
Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. HRR alterations have also been identified, albeit less frequently, in other human malignancies including triple negative breast, prostate, and pancreatic cancers. The most commonly altered HRR genes are BRCA1 and BRCA2 followed by other Fanconi Anemia (FA) genes (e.g. PALB2, FANCA, FANCI, FANCL, and FANCC), core RAD genes (e.g. RAD50, RAD51, RAD51C, and RAD54L) and DNA damage response genes involved in HRR, such a...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: D'Andrea, A. D. Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research
Abstract B25: "TargetDBR"--A DNA repair drug and target discovery collaboration: Exploiting synthetic lethal, high content, and functional cellular reporter assays to accelerate DNA repair targeted drug discovery
Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Inhibition of DSB repair sensitizes cells to these therapies. Mutations have been reported in nearly every DNA repair pathway and these pathways often exhibit redundancy. Inhibition of functional repair factors can induce synthetic lethality in repair-deficient tumors even in the absence of exogenous DNA damage and whilst sparing healthy tissue. We demonstrate a compound and target discovery platform comprising the integration...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hollick, J. J., Abriola, L., Bono, F., Hegan, D., Klingbeil, P., Liu, Y., Sundaram, R., Surovtseva, Y. V., Whittaker, M., Bindra, R. S., Glazer, P. M. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A25: Investigating the co-occurrence of potentially pathogenic DNA repair pathways alleles in BRCA1 or BRCA2 mutation carrier women with ovarian cancer.
Recurrent mutations in BRCA1 and BRCA2, which are genes that play a major role in the homologous recombination (HR) DNA repair pathway, account for a significant proportion of hereditary breast cancer (HBC) and or breast-ovarian cancer (HBOC) families of French Canadian (FC) descent due to common founders. This has facilitated genetic testing for establishing germline mutation carrier status in hereditary cancer clinics in Quebec for offering cancer surveillance and prevention options for women at risk for hereditary breast and other cancers. Recent evidence suggests that rare germline mutations in other members of HR path...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Alenezi, W. M., Revil, T., Badescu, D., Arcand, S. L., Rouleau, G., Ragoussis, I., Tonin, P. N. Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA24: Targeting Chk1
The majority of traditional anticancer drugs inhibit DNA synthesis either by directly damaging DNA or by inhibiting synthesis of deoxyribonucleotide precursors. DNA damage induces cell cycle arrest through activation of cell cycle checkpoints whose goal is to prevent further DNA synthesis or mitosis until the damage is repaired. These checkpoints have undergone intense investigation as potential therapeutic targets, and Chk1 inhibitors (Chk1i) have emerged as promising novel therapeutic agents (1). Chk1 was initially recognized as a regulator of the DNA damage-induced S and G2 checkpoints, and its inhibition forced S phase...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Eastman, A. R. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research
Abstract B24: Genomic prediction of response to PARP inhibition in breast cancer
In conclusion, we identified a gene set involved with DNA repair, cell-cycle, and programmed cell death, which was associated with poor outcomes in triple-negative breast cancer patients that could potentially benefit from anti-PARP therapy.Citation Format: Saima Hassan, Amanda Esch, Laura M. Heiser, Joe W. Gray. Genomic prediction of response to PARP inhibition in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B24. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Hassan, S., Esch, A., Heiser, L. M., Gray, J. W. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A24: A genome-wide RNAi screen identifies synthetic lethality of CX-5461 with homologous recombination repair deficiency in ovarian cancer
Cancer is characterized by deregulated cell growth and proliferation, both of which are associated with hyperactivation of ribosome biogenesis. Inhibition of ribosome biogenesis using CX-5461, a specific inhibitor of RNA polymerase I-dependent transcription, has shown therapeutic efficacy in a MYC driven B-cell lymphoma mouse model, which is enhanced when used in combination with the mTORC1 inhibitor Everolimus. However, the therapeutic potential of CX-5461 in solid cancers is yet to be determined.Our preliminary data utilizing a panel of 36 ovarian cancer (OVCA) cell lines suggest that acute CX-5461 treatment results in c...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Yan, S., Chan, K. T., Simpson, K. J., Sanij, E., Sheppard, K. E., Hannan, K. M., Hannan, R. D., Pearson, R. B. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA23: Using PARP inhibitors to target ATM-deficient cancers
The Ataxia-Telangiectasia Mutated (ATM) serine/threonine protein kinase plays an important role in orchestrating the cellular response to DNA double strand breaks (DSBs). Germline loss of ATM function results in Ataxia-Telangiectasia (A-T), a devastating childhood syndrome characterized by progressive loss of neuromuscular control, immune deficiency and cancer predisposition. ATM is also deleted in a large proportion of human mantle cell lymphoma (MCL) and other lymphomas and recent studies have revealed that ATM is altered in many sporadic cancers including lung, colorectal, breast and prostate cancer. We previously showe...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lees-Miller, S. P. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research
Abstract A23: BRCA1 mutations in the BRCT domain can be removed through alternative splicing and induce PARP inhibitor resistance
Conclusions: Our findings indicate that alternative splicing can remove deleterious mutations that disrupt BRCT peptide folding, generating more truncated but functional proteins capable of restoring residual DNA repair and PARPi resistance.Citation Format: Yifan Wang, Andrea J. Bernhardy, Neil Johnson. BRCA1 mutations in the BRCT domain can be removed through alternative splicing and induce PARP inhibitor resistance [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Wang, Y., Bernhardy, A. J., Johnson, N. Tags: Synthetic Lethality and Viability: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA22: The role of ATM in tumor and endothelial cells in mediating the response of cancer to radiation therapy
Fibroblasts isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation and mice lacking the gene mutated in ataxia telangiectasia (ATM) are sensitive to total-body irradiation. Kinase inhibitors of ATM can sensitize tumor cells to radiation, but these inhibitors may also sensitize normal tissues to radiation toxicity. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but whether endothelial cell death plays an important role in tumor response to radiation therapy has remained unclear. To clarify the role of endothelial cells i...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Kirsch, D. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research
Abstract PR21: DEK is critical for homologous recombination and its loss is synthetic lethal with DNA-PK inhibition
DEK is a highly conserved chromatin-bound protein whose upregulation across different cancer types directly correlates with genotoxic therapy resistance. While DEK loss induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair, the role of DEK remains incompletely understood. To this end we previously determined that loss of DEK moderately attenuates non-homologous end-joining repair (NHEJ). However, the observed partial decrease in NHEJ activity is likely insufficient to fully explain the sensitivity of DEK-deficient cells to radiation and chemotherapy. Thus, we h...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Smith, E. A., Gole, B., Willis, N. A., Eric, K. F., Jegga, A. G., Ali, A. M., Guo, H., Meetei, A. R., Andreassen, P. R., Kappes, F., Scully, R., Wiesmüller, L., Susanne, W. I. Tags: Homologous Recombination Defects: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA21: Targeting WEE1 kinase to potentiate chemoradiation in the treatment of pancreatic cancer
Pancreas cancer is projected to cause approximately 42,000 deaths in 2016, making it the third greatest cause of cancer mortality (behind lung and colorectal, but greater even than breast). Systemic failure remains the dominant cause of death, although local failure is responsible for up to 1/3 of the pancreatic cancer related mortality. We have focused on improving the treatment of locally advanced pancreatic cancer, defined as disease which cannot be resected but has not overtly metastasized, where the issue of local control becomes even more important, and have hypothesized that the treatment of locally advanced pancrea...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lawrence, T. S., Morgan, M. A. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research
Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Burgenske, D., Mladek, A., Sarkaria, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
