Abstract A38: Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy
Conclusions: PARP inhibitors, developed primarily to target vulnerabilities in tumor cells directly, may provide additional anti-tumor effects via DDSP and repurposing PARPi to suppress the DDSP could augment responses to radiation and chemotherapy via microenvironment modulation. In addition to PARP1, our ongoing studies are designed to evaluate other PARP family members including PARP5 and PARP10 that may influence damage responses.Citation Format: Payel Chatterjee, Peter Nelson. Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy [abstract]. In: Proceedings of the AACR Spec...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Chatterjee, P., Nelson, P. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B37: PARP inhibitor olaparib induces genomic instability in normal mammalian cells
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA damage response pathways to be targeted by specific inhibitors for clinical benefit. Tumors with defects in homologous recombination (HR) are hypersensitive to PARP inhibitors (PARPi), and early phase clinical trials have been promising in patients with advanced BRCA1 and BRCA2-associated breast, ovary and prostate cancer. Unlike HR-defective cells, HR-proficient cells manifest low cytotoxicity when exposed to PARPi. Nonetheless, they mount a DNA damage response and show a genomic instability phenotype as demonstrated by an increased frequ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Vanoli, F., Ito, S., Frock, R. L., Alt, F. W., Moynahan, M. E., Jasin, M. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A37: Development of screening methods to identify Translesion DNA Synthesis inhibitors
Translesion DNA synthesis (TLS) is a DNA damage tolerance process that employs specialized polymerases to bypass DNA damage during replication. Recent evidence indicates that TLS is a key process that promotes the development of resistance to cancer treatments that induce DNA damage (i.e. Cisplatin). Thus, the inhibition of TLS emerges as a promising strategy for cancer therapy. However, to date, specific chemical inhibitors of TLS are not available.The main goal of our project is to identify specific inhibitors of TLS that can be used as a proof of concept in cancer therapy by developing cell-based assays that explore TLS...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Villafanez, F., Garcia, A. I., Pansa, M. F., Carbajosa, S., Bocco, J. L., Soria, G. Tags: Replication Stress: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B36: Targeting BRCA1 through natural HSP90 inhibitors to reverse platinum resistance in TNBC
Background: Triple-negative breast cancers (TNBCs) are highly associated with an aggressive clinical course, resistance to chemotherapy, and poor prognosis compared to other breast cancer subtypes. However, breast cancers arising in BRCA1 mutation carriers appear to be particularly sensitive to platinum-based chemotherapy agents. The tumor suppressor BRCA1 (breast cancer type 1 susceptibility protein) is part of a protein complex that repairs DNA damage by homologous recombination. Recent studies have shown that tumor cells expressing high levels of BRCA1 are resistant to both ionizing radiation (IR) and platinum-based che...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Valdez, K., Ramamoorthy, P., Anant, S., Jensen, R. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B34: Development of novel small molecule inhibitors targeting DNA repair proteins
More than 1.6 million new cases of cancer will be diagnosed in the US in 2016 and a third of these will be from solid tumor of the lung, pancreas, breast, and ovary. These cancers represent a continuing clinical challenge in treatment and together account for over 250,000 deaths in the US alone, representing over 40% of all cancer deaths. There are limited therapeutic options for these patients, and targeted and combination therapies remain necessary for treating these aggressive cancers. The opportunity exists to exploit recent scientific advances in our knowledge of the underlying biology behind these cancers to create n...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Pawelczak, K. S., Gavande, N., VanderVere-Carozza, P., Turchi, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B33: PARP-dependent co-modulation of DNA repair and microglial activity as a dual-pronged anti-glioblastoma treatment strategy
Conclusion: Preliminary results show that Olaparib is effective in sensitizing GBM cells to chemotherapy while microglia appear to enhance this effect. Further studies linking this combination therapy with microglia-mediated GBM elimination will help to elucidate the mechanism of this bimodal effect. This study emphasizes the importance of: (1) identifying novel effects of PARP inhibition on microglia in association with GBM and (2) the importance of developing microglia-mediated immunotherapeutic intervention to overcome the limitations of current therapies to significantly improve patient outcome.Citation Format: Asha Si...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Sinha, A., Katyal, S., Kauppinen, T. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A33: Defect in S phase cell cycle checkpoint renders tumours vulnerable to CHK1 inhibitor single-agent treatment in vitro and in vivo
CHK1 inhibitors are being investigated as chemosensitizing agents with agents that increase replication stress. Here we have investigated the molecular basis of sensitivity to CHK1 inhibitors as single agents in melanoma and lung cancer. We have found that sensitivity in vitro and in vivo to single agent CHK1 inhibitor is loss of the S phase cell cycle checkpoint response. This is through a number of mechanisms including the uncoupling of CHK1 activation with the destabilization of CDC25A. Loss of checkpoint by over-expressing components of the checkpoint or inhibition of Wee1, covert CHK1 inhibitor insensitive cells to se...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Oo, Z. Y., Stevenson, A., Lanagan, C., Spoerri, L., Larsen, J., Gabrielli, B. Tags: Replication Stress: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B32: CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, combined with DDR agents provides a novel approach to increasing therapeutic index
Topoisomerase I inhibitors are used as standard-of-care chemotherapy in many types of cancer but are associated with significant toxicities. There is potential to improve their efficacy further by combining with inhibitors of the DNA damage response, such as the poly ADP ribose polymerase (PARP) inhibitor olaparib. However, while preclinical data highlight the improved efficacy of this combination, subsequent clinical trials have struggled due to dose limiting myelotoxicity.CRLX101 is an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a potent topoisomerase I inhibitor. This agent is ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: O'Connor, L. O., Wang, A. T., Jones, D., Odedra, R., Spreadborough, M., Wilson, J., Smith, A., Cotton, P., Reens, J., Barnes, J., Sheridan, V., Tellez, A., Lau, A., Sadler, C., O'Connor, M. J., Eliasof, S. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A32: Exploring the interplay between nucleotide excision repair and DNA replicative stress
Ultraviolet (UV) light causes highly genotoxic DNA lesions that are removed by nucleotide excision repair (NER), and NER is critical for preventing UV-associated skin cancers. UV-induced DNA lesions block the progression of DNA polymerases, leading to replicative stress and genomic instability. Upon UV, the ataxia-telangectasia and rad3 related (ATR) kinase is rapidly activated, leading to cell-cycle arrest, inhibition of replication origin firing, and stabilization of blocked replication forks. Intriguingly, previous data indicated that reduced ATR activity causes profound NER defects specifically in S phase cells. Moreov...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Drobetsky, E., Belanger, F., Angers, J.-P., Fortier, E., Costantino, S., Wurtele, H. Tags: Replication Stress: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B31: Poly(ADP-ribose) Polymerase 1 as a novel target for alpha-particle therapy in high-risk neuroblastoma
Conclusion: 211At-MM4 is a small molecule PARP inhibitor functionalized with an alpha emitting radionuclide astatine-211 that can effectively deliver alpha-particles to the nucleus of cancer cells. The neuroblastoma cell lines evaluated showed differential sensitivities and in vitro results translated into in vivo models. Furthermore we have characterized a novel therapy for high-risk neuroblastoma and aim for future clinical translation.Citation Format: Mehran Makvandi, Catherine Hou, Kuiying Xu, Redmond-Craig Anderson, Samuel Ander-Effron, Robert H. Mach, John M. Maris, Daniel A. Pryma. Poly(ADP-ribose) Polymerase 1 as a...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Makvandi, M., Hou, C., Xu, K., Anderson, R.-C., Ander-Effron, S., Mach, R. H., Maris, J. M., Pryma, D. A. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B30: Talazoparib efficacy is enhanced by noncytotoxic doses of temozolomide-mediated DNA damage in prostate cancer cell lines
Conclusion: Talazoparib is cytotoxic to prostate cancer cells as a single agent in nonclinical cell based models. Herein, we demonstrate that combining noncytotoxic doses of TMZ with talazoparib improves efficacy in killing of LNCaP and 22RV1 cells. The increased efficacy corresponds with increased DNA-damage and increased trapped PARP-DNA complexes. Low, noncytotoxic doses of TMZ are shown to generate DNA damage sites in vitro and in treated LNCaP cells, providing a mechanistic basis for the combination effect of talazoparib and TMZ. Together, these nonclinical data provide scientific rationale for a clinical trial strate...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lindquist, J. N., Phan, V. T., Riquelme, E., Mukherjee, K., Farias, O., Gupta, A., Raja, M., Rai, R., Uppal, H., Protter, A. A. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A28: Mutational landscape of TP53 in localized prostate cancer
Conclusions: This is the first comprehensive interrogation of the mutational landscape of TP53 in localized prostate cancer. Our findings suggest that functional TP53 loss at both the copy number and transcription level accounts for a subset of non-indolent localized prostate cancer.Citation Format: Osman Mahamud, Melvin L.K Chua, Stephane Supiot, Emilie Lalonde, Alan Dal Pra, Alejandro Berlin, Michèle Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Yves Fradet, Bernard Têtu, Gaetano Zafarana, Alice Meng, Julie Livingstone, Melania Pintilie, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Br...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Mahamud, O., Chua, M. L. K., Supiot, S., Lalonde, E., Pra, A. D., Berlin, A., Orain, M., Picard, V., Hovington, H., Bergeron, A., Fradet, Y., Tetu, B., Zafarana, G., Meng, A., Livingstone, J., Pintilie, M., Fraser, M., Kwast, T. v. d., Boutros, P. C., Rob Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA27: Exploiting the inhibition of cullin-RING-ligases in DSB repair as a therapeutic strategy
While single component E3 ubiquitin ligases have established roles in DNA double-strand break (DSB) repair, the function of multicomponent cullin-RING-ligases (CRL) in DSB repair is only beginning to emerge. FBXW7 is a substrate recognition component of Skp1-Cullin1-F-box E3 ubiquitin ligases previously known only to regulate the proteasomal degradation of substrates such as Cyclin E and MCL1. Given that FBXW7 loss promotes genomic instability, we hypothesized that FBXW7 may have a direct function in DSB repair. To establish the functions of FBXW7 in DSB repair, we first demonstrated the rapid localization of FBXW7 to DSB ...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Morgan, M. Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research
Abstract B27: Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against malignant brain tumors
Conclusions: ATM and TDP1 co-inhibition represents an effective two-pronged approach to chemoradiosensitize CNS tumors. As TDP1 antagonizes Top1cc formation and efficacy of Top1 poisons such as the camptothecin (CPT) cohort of drugs, our findings will improve existing Top1-mediated anti-cancer strategies by enhancing tumor cell killing while reducing clinical doses and patient side-effects. Furthermore, these findings also suggest an alternative avenue in the clinical management of GBM.Citation Format: Matthew Packer, Ali Saleh, Sachin Katyal. Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against mal...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Packer, M., Saleh, A., Katyal, S. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A27: Assessing somatic tumor-associated RAD51 mutations and screening for novel dominant-interfering RAD51 proteins
The responsiveness of cancer cells to chemotherapy and targeted treatment, as well as the development of resistance, is determined by the state of DNA damage response pathways. Homology-directed repair (HDR) is crucial for error-free repair of DNA double-strand breaks that arise during replication stress or are induced by exogenous genotoxins. Therefore, HDR efficacy status in cancer cells could potentially be utilized as an indicator to predict tumor responsiveness to standard chemotherapies and to poly(ADP-ribose) polymerases (PARP) inhibitors. We are interested in understanding the influence of different levels of funct...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Lim, P. X., Sutherland, J., Noonan, R., Dananberg, A., Holloman, W., Smogorzewska, A., Jasin, M. Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research
