Molecular Cancer Therapeutics最新文献

{"title":"Tumor microenvironment reprogramming improves nanomedicine-based chemo-immunotherapy in sarcomas.","authors":"Antonia Charalambous, Fotios Mpekris, Myrofora Panagi, Chrysovalantis Voutouri, Christina Michael, Alberto A Gabizon, Triantafyllos Stylianopoulos","doi":"10.1158/1535-7163.MCT-23-0772","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0772","url":null,"abstract":"<p><strong>Background/introduction: </strong>Sarcomas are a heterogenous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases makes treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which lead to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher, toxic doses of chemotherapy. Here, we tested the mechanotherapeutic ketotifen combined with either pegylated-liposomal doxorubicin (PLD) or pegylated-liposomal co-encapsulated alendronate-doxorubicin (PLAD) plus anti-PD-1 antibody in mouse models of fibrosarcoma and osteosarcoma.</p><p><strong>Results: </strong>We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave-elastography (SWE) and contrast-enhanced-ultrasound (CEUS) respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. An additional observation was a trend to improved antitumor response when nano-chemotherapy is given alongside anti-PD1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy, increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper-cell and decreased the number of regulatory-T-cells. In addition, the combination also altered the polarization of tumor associated macrophages, favouring the M1 immune-supportive phenotype over the M2 immuno-suppressive phenotype.</p><p><strong>Conclusion: </strong>Collectively, our findings provide evidence that ketotifen-induced TME reprograming can improve the efficacy of nanomedicine-based chemoimmunotherapy in sarcomas.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The discovery of a potent PARP1 inhibitor Senaparib.","authors":"Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Mingchuan Guo, Yangzhen Jiang, Ye E Tian","doi":"10.1158/1535-7163.MCT-23-0625","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0625","url":null,"abstract":"<p><p>Poly (ADP-ribose) polymerases 1 (PARP1) is a critical enzyme involved in DNA damage repair. It belongs to a super family of proteins and catalyzes poly (ADP-ribosyl)ation (PARylation). PARP1 inhibitors are effective to treat tumors that have homologous recombination deficiency (HRD) such as the ones with BRCA1/2 mutations. The PARP1 inhibitors that have been approved by FDA inhibit both PARP1 and PARP2. PARP2 has also been suggested to have similar function in DNA repair as PARP1. In addition to inhibiting PARP1 enzymatic activities, PARP1 inhibitors also cause PARP1 enzyme to be \"trapped\" on DNA which leads to DNA replication fork to stall and eventually double-strand DNA breaks and cell death. Here, we report a PARP1 inhibitor, Senaparib, which has a novel chemical structure and high potency inhibiting PARP1/2 enzymes. Senaparib was highly potent in cell viability tests against tumor cells with BRCA1/2 mutations. It was efficacious in CDX and PDX xenograft models in tumor harboring BRCA1/2 mutations. In combination studies, Senaparib used with temozolomide (TMZ) had shown strong synergistic cytotoxicity in both in vitro and in vivo experiments. Senaparib represents a novel class of PARP1 inhibitors that can be used for the treatment of cancer. A phase III clinical study of Senaparib for maintenance treatment following first-line chemotherapy in patients with advanced ovarian cancer has met its primary endpoint, and a new drug application of Senaparib has been accepted by National Medical Products Administration (NMPA) of China for review.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Monovalent Direct Degraders of BRD4 That Act Via the Recruitment of DCAF11.","authors":"Gregory S Parker, Julia I Toth, Sarah Fish, Gabrielle A Blanco, Taylor Kampert, Xiaoming Li, Linette Yang, Craig R Stumpf, Kenneth Steadman, Aleksandar Jamborcic, Stephen Chien, Elizabeth Daniele, Alejandro Dearie, Geoffray Leriche, Simon Bailey, Peggy A Thompson","doi":"10.1158/1535-7163.MCT-24-0219","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0219","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent \"direct\" degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extra-terminal (BET) protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent anti-tumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent anti-tumor activity in vivo.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Chemoresistance in Advanced Bladder Cancers with a Novel Adjuvant Strategy.","authors":"Juliette R Seremak, Kunj Bihari Gupta, Sunilkanth Bonigala, Elise Liu, Brendan Marshall, Wenbo Zhi, Riham M Bokhtia, Siva S Panda, Vinata B Lokeshwar, Bal L Lokeshwar","doi":"10.1158/1535-7163.MCT-23-0806","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0806","url":null,"abstract":"<p><p>Advanced urinary bladder cancer is characterized by rapid progression and development of therapy resistance. About 30% of the patients are diagnosed with high-grade tumors (grade > T2a). A typical nonsurgical treatment is systemic chemotherapy using cisplatin (C) and gemcitabine (G). However, treatment failure and subsequent disease progression are common in treated patients, and adjuvant therapies are not significantly effective. The therapeutic potential of a molecular hybrid of ursolic acid (UA), a pentacyclic-triterpene conjugated to N-methyl piperazine (UA4), was tested on both naïve (WT) and gemcitabine-resistant (GemR) variants of two human invasive bladder cancer cell lines, 5637 and T24. UA4 killed 5637 (4 µmol/L), T24 (4 µmol/L) WT, and GemR cells in vitro at equal potency. Pretreatment with UA4 followed by G synergistically killed WT and GemR cells by >50% compared with G followed by UA4. Oral gavage of UA4 (100 mg/kg) inhibited WT and GemR tumor growth in athymic mice. UA4 + G was more effective against GemR tumors than either drug alone. Studies revealed cytotoxic autophagy as a mechanism of UA4 cytotoxicity. UA4 induced moderate apoptosis in T24 but not in 5637 cells. Mitochondrial integrity and function were most affected by UA4 because of high levels of reactive oxygen species, disruption of mitochondrial membrane, and cell cycle arrest. These effects were enhanced in the UA4 + G combination. UA4 was well-tolerated in mice, and oral gavage led to a serum level >1 µmol/L with no systemic toxicity. These results show the potential of UA4 as a nontoxic alternative treatment for high-grade bladder cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining EHMT and PARP Inhibition: A Strategy to Diminish Therapy-Resistant Ovarian Cancer Tumor Growth while Stimulating Immune Activation.","authors":"Lily L Nguyen, Zachary L Watson, Raquel Ortega, Elizabeth R Woodruff, Kimberly R Jordan, Ritsuko Iwanaga, Tomomi M Yamamoto, Courtney A Bailey, Francis To, Abigail D Jeong, Saketh R Guntupalli, Kian Behbakht, Veronica Gibaja, Nausica Arnoult, Alexis Cocozaki, Edward B Chuong, Benjamin G Bitler","doi":"10.1158/1535-7163.MCT-23-0613","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0613","url":null,"abstract":"<p><p>Despite the success of poly-ADP-ribose polymerase inhibitors (PARPi) in the clinic, high rates of resistance to PARPi presents a challenge in the treatment of ovarian cancer, thus it is imperative to find therapeutic strategies to combat PARPi resistance. Here, we demonstrate that inhibition of epigenetic modifiers euchromatic histone lysine methyltransferases 1/2 (EHMT1/2) reduces the growth of multiple PARPi-resistant ovarian cancer cell lines and tumor growth in a PARPi-resistant mouse model of ovarian cancer. We found that combinatory EHMT and PARP inhibition increases immunostimulatory double-stranded RNA formation and elicits several immune signaling pathways in vitro. Using epigenomic profiling and transcriptomics, we found that EHMT2 is bound to transposable elements, and that EHMT inhibition leads to genome-wide epigenetic and transcriptional derepression of transposable elements. We validated EHMT-mediated activation of immune signaling and upregulation of transposable element transcripts in patient-derived, therapy-naïve, primary ovarian tumors, suggesting potential efficacy in PARPi-sensitive disease as well. Importantly, using multispectral immunohistochemistry, we discovered that combinatory therapy increased CD8 T-cell activity in the tumor microenvironment of the same patient-derived tissues. In a PARPi-resistant syngeneic murine model, EHMT and PARP inhibition combination inhibited tumor progression and increased Granzyme B+ cells in the tumor. Together, our results provide evidence that combinatory EHMT and PARP inhibition stimulates a cell autologous immune response in vitro, is an effective therapy to reduce PARPi-resistant ovarian tumor growth in vivo, and promotes antitumor immunity activity in the tumor microenvironment of patient-derived ex vivo tissues of ovarian cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B004: An isogenic CRISPR screen identifies novel MYC-driven vulnerabilities","authors":"Peter Lin, Linda Penn","doi":"10.1158/1538-8514.synthleth24-b004","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b004","url":null,"abstract":"\u0000 c-MYC (MYC) is a central regulatory protein that is dysregulated in >50% of all human cancers and is linked to aggressive disease. Developing MYC inhibitors would revolutionize cancer treatment; however, developing small molecules that directly target MYC is challenging. An alternative approach is to identify and inhibit critical MYC partner proteins to inactivate MYC and trigger cancer cell death. Inhibiting these targets therapeutically can result in synthetic lethality (MYC-SL), which can be exploited in MYC-dysregulated cancers. To identify MYC-SL targets, we performed a genome-wide CRISPR knock-out screen using an isogenic pair of normal and MYC-driven breast cancer cells. In contrast to other screens, this model is dependent on MYC and recapitulates human disease at both pathological and molecular levels in vivo. We identified high-priority hits to validate from the screen using two independent approaches: 1) a traditional gene-set enrichment analysis to identify highly represented biological pathways; and 2) analyzing the Cancer Dependency Map (DEPMAP) to select hits that are likely to be robust beyond the context of our screening conditions. Using a traditional gene-set enrichment analysis approach, we identified topoisomerase 1 (TOP1) as an actionable vulnerability that can be targeted with clinically approved inhibitors. Genetic and pharmacological inhibition of TOP1 resulted in MYC-driven cell death compared to that in control cells. Finally, drug response to TOP1 inhibitors significantly correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids, highlighting TOP1 as a promising target for MYC-driven cancers. As a secondary approach to interpreting our CRISPR screen hits, we analyzed DEPMAP to identify MYC-SLs that are differentially essential in MYC-dependent cancer cells. Specifically, data from RNA interference screens in hundreds of cancer cell lines were used to describe the response of these cells to MYC knockdown. These data were used to define MYC-dependent and MYC-independent cell lines within the context of this analysis. These two groups were then investigated for their in silico response to the knockdown of each of our MYC-SL hits. MYC-SLs, which were also differentially essential in MYC-dependent cancer cells from DEPMAP, were prioritized for further investigation. Critical MYC cofactors that have been validated by us and others (e.g., CDK9) were identified, providing confidence in this approach, and rationalizing ongoing investigations. Together, this work features two successful strategies to prioritize hits from hundreds of synthetic-lethal genome-wide CRISPR screens to identify novel MYC-driven vulnerabilities in cancer.\u0000 Citation Format: Peter Lin, Linda Penn. An isogenic CRISPR screen identifies novel MYC-driven vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilitie","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141364922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR009: Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal cancers","authors":"Tim Arnoldus, Alex van Vliet, Adriaan F.H. de Groot, Niek Blomberg, Onno B. Bleijerveld, Susan E. van Hal-van Veen, Anita E. Grootemaat, Rolf Harkes, N. N. van der Wel, Maarten Altelaar, Martin Giera, D. Peeper","doi":"10.1158/1538-8514.synthleth24-pr009","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-pr009","url":null,"abstract":"\u0000 Synthetic lethal interactions (SLIs) can provide a therapeutic index, as illustrated by PARP inhibition of BRCA-deficient cancers. This clinical success, and other examples, have spurred efforts to identify additional cancer-associated SLIs. Whereas additional SLIs based on genomic alterations in cancer have been identified, we set out to explore the SLI space as a function of differential RNA expression profiles in cancer and normal tissue, covering all ∼3.4e8 gene pairs. In our bioinformatic pipeline, synthetic lethality is scored by correlating DepMap dependency and expression data (n = 913 cancer cell lines), while cancer specificity is scored by comparing TCGA expression data for 9264 tumors and 741 healthy samples. Cancer specificity is confirmed by comparing also calibrated GTEx data for 17382 healthy tissue samples with calibrated DepMap expression data. With this pipeline we uncovered a frequent cancer-specific SLI between the paralogs cytidine diphosphate diacylglycerol synthase 1 (CDS1) and CDS2 (p<0.001 in all three analyses). Essentiality of CDS2 is observed in one third of cultured cancers (DepMap). Using CRISPR-Cas9 we confirm the CDS1-dependency for CDS2 essentiality in a panel of 12 cultured cancer cell lines, with lethality by CDS2 ablation reaching up to 98% in CDS1-negative cell lines. We also confirm the SLI using admixing experiments in tumor-bearing mice for two cell lines (6 mice per group, up to 95% synthetic lethality, p<0.001). The essentiality of CDS2 for cell survival is observed for mesenchymal-like cancers, which commonly express low levels of CDS1. To biochemically define the effects of CDS2 perturbation in CDS1-negative cancer cells, we performed multi-omic analyses in a panel of CDS1-negative cancer cell lines. The results show that mechanistically, the CDS1-2 SLI is accompanied by disruption of lipid homeostasis, including extensive accumulation of cholesterol esters and triglycerides. Additionally, quantitative western blotting for cleaved caspase-3 showed induction of apoptotic cell death (p<0.001 in 2 cell lines). To challenge the robustness of the SLI, we performed genome-wide CRISPR-Cas9 knockout screens in a panel of four CDS1-negative cancer cell lines. This failed to identify a common escape mechanism of death caused by CDS2 ablation. These findings suggest that no common escape to the combined loss of CDS1 and CDS2 is possible through loss-of-function. In conclusion, by computational, genetic, biochemical and functional analyses we demonstrate that CDS2 may serve as a target in mesenchymal cancers, meriting therapeutic exploration.\u0000 Citation Format: Tim Arnoldus, Alex van Vliet, Adriaan F.H. de Groot, Niek Blomberg, Onno B. Bleijerveld, Susan E. van Hal-van Veen, Anita E. Grootemaat, Rolf Harkes, Nicole N. van der Wel, Maarten Altelaar, Martin Giera, Daniel S. Peeper. Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal cancers [abstract]. In: Proceedings of the A","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141366442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B027: A pathway-informed framework to infer synthetic lethal relationships in pediatric cancer","authors":"Anastasia Spinou, Richard Gremmen, Puck Veen, J. Drost, P. Kemmeren","doi":"10.1158/1538-8514.synthleth24-b027","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b027","url":null,"abstract":"\u0000 Synthetic lethality, the combination of two mutated genes which results in cell death, has been greatly investigated due to its therapeutic potential in cancer. Despite the common practice of experimentally detecting synthetic lethality, here we extend a computational framework that employs co-occurrence of gene mutations to infer synthetic lethality by incorporating pathways. Pathways aggregate the mutated genes into a functional unit and give power to uncover relationships containing genes of low mutation frequency e.g. in pediatric cancer, which otherwise would not be observed by testing individual gene pairs. Our proposed framework is an alternative avenue to a more focused synthetic lethality search by exploiting mutation data & pathway knowledge. We infer potentially synthetic lethal relationships based on mutated gene co-occurrence. A less often than expected co-occurrence, or so-called mutual exclusivity (ME), indicates a potentially synthetic lethal relationship whereas one that occurs more often than expected (CO) indicates a potentially advantageous relationship. In this framework we use a selected set of biological pathways from Reactome to aggregate gene mutations per pathway for each individual tumor (SNVs and indels with high/moderate impact) within two public pediatric cancer datasets, TARGET and DKFZ. This results in mutated-pathway profiles per tumor which are tested for co-occurrence using rediscover. The test outputs significant co-occurring and mutually exclusive pathways from which we extract the underlying mutated gene pairs. The co-occurring and mutually exclusive gene pairs are then annotated for pathway epistasis, protein complexes and their presence in BioGRID and SynLethDB. Finally, the validity of the proposed gene pairs is examined in literature. The test detected 439 (ME: 369, CO:70) significant pathway pairs in TARGET and 49 (ME: 31, CO:18) in DKFZ across several cancer types. Out of these, 3185 gene pairs were extracted in TARGET (ME: 2671, CO: 514) and 331 (ME: 16, CO: 315) in DKFZ. These relationships are significantly more than the ones found when testing solely for gene pairs. Pathways aid in partially decreasing findings due to subtype or pathway epistasis. For example, FLT3-KRAS found in TARGET-B-ALL by the gene test is not detected by the pathway test. The test was, also, able to uncover mutually exclusive (ME) gene pairs in smaller datasets. The initially found ME genes TP53-DROSHA in Wilms tumors and KIT-NRAS in AML tumors in TARGET by the gene test, were detected in the corresponding cancer types’ DKFZ datasets. In addition to TP53-DROSHA, TP53-DGCR8 were found ME in Wilms tumors of DKFZ, indicating the microprocessor complex mutations ME to TP53 mutations. To sum up, we present a pathway-informed synthetic lethality inference framework for pediatric cancer to explore synthetic lethal relationships and other complex functional relationships between mutated genes by exploiting already existing data and ","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141365795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B012: Predicting targetable paralog synthetic lethalities and functional redundancies in cancer genomes","authors":"Rohan Dandage, Elena Kuzmin","doi":"10.1158/1538-8514.synthleth24-b012","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b012","url":null,"abstract":"\u0000 Paralogs are prevalent in the human genome and are considered a rich source of synthetic lethality due to functional redundancy. For a cancer cell carrying a gene with Loss-Of-Function (LOF) mutation, inactivation of its paralog using gene editing can induce a selective decrease in viability, leaving normal cells that do not harbor the mutation unharmed. Previous studies have exploited this vulnerability of cancer genomes. However, the cancer-specificity of such synthetic lethality limits its application across different cancer types. Furthermore, the role of functional redundancy which can explain the cancer specificity has remained largely unexplored. In this study, we computationally predicted synthetic lethal paralogs along with mechanistically important functional redundancies between them in a cancer-specific manner. We applied our prediction method to publicly available data for an aggressive subtype of breast cancer called triple-negative breast cancer (TNBC), which lacks the expression key biomarkers and hence has the worst prognosis among other breast cancer subtypes. TNBC is characterized by the highest mutational load and the largest fraction of genome altered among the breast cancer subtypes providing a rich mutational landscape to identify LOF genes. Using the CRISPR inactivation screen data for cancer cell lines obtained from the Cancer Dependency Map (DepMap) project, we predicted sets of synthetic lethal paralogs that show a significantly greater viability decrease if a gene carries LOF and its paralog is inactivated, compared to the viability decrease due to the inactivation of only one of the paralogs. Consistent with previous findings of context-dependent synthetic lethality, we found that a relatively small fraction of TNBC-specific synthetic lethal paralogs overlapped with those found across other cancer types. To uncover the mechanistically important functional redundancies between paralogs, we analyzed the genomics and transcriptomics data from multiple sources: TNBC panel of primary tumors and patient-derived xenografts, Pan-Cancer Analysis of Whole Genomes (PCAWG), and the Cancer Cell Line Encyclopedia (CCLE). The functional redundancies varied across cancer types based on (1) mutual exclusivity of LOFs, (2) backup compensation of deleterious mutations, (3) backup upregulation, and (4) dosage balance. Overall, our findings show a strong context-dependency of synthetic lethal paralogs and estimates of functional redundancy, emphasizing the importance of such cancer-specific predictions in identifying targetable paralog synthetic lethalities. Collectively, the computational method and sets of targetable paralogs are a unique resource for developing precision oncology therapeutic strategies against TNBC and other cancers more broadly.\u0000 Citation Format: Rohan Dandage, Elena Kuzmin. Predicting targetable paralog synthetic lethalities and functional redundancies in cancer genomes [abstract]. In: Proceedings of the AACR Speci","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141364585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA017: Synthetic dependencies arising during tumor evolution","authors":"Kris C. Wood","doi":"10.1158/1538-8514.synthleth24-ia017","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-ia017","url":null,"abstract":"\u0000 Our research focuses on defining tumor-selective survival dependencies and understanding how these dependencies change during tumor evolution. In this talk, I will provide an overview of our lab’s work, highlighting recent and ongoing studies uncovering mechanism-based synthetic lethalities arising in residual and fully drug resistant tumors whose therapeutic exploitation has the potential to select against the most aggressive forms of disease.\u0000 Citation Format: Kris C. Wood. Synthetic dependencies arising during tumor evolution [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA017.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141364938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}