DDR

P2, N=51, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=112 --> 51 | Trial completion date: Mar 2027 --> Dec 2027 | Recruiting --> Suspended | Trial primary completion date: Mar 2024 --> Dec 2024

P2, N=130, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=1000 --> 130 | Trial primary completion date: Apr 2024 --> Dec 2024

In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Together with defective cell cycle checkpoints reported previously, this DNA repair deficiency in H3.3-G34W cells led to accumulation of micronuclei and cytosolic DNA following IR, which subsequently led to activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immune-stimulatory cytokines. These findings suggest a potential for radiotherapy for tumors expressing H3.3-G34W, which can be further improved by combination with STING agonists to induce immune-mediated therapeutic efficacy.

This is the first study to map the profile of germline mutations in patients with MPMs involving lung cancer. This study may shed light on early prevention and novel targeted therapies for MPMs involving lung cancer patients with HJR mutations.

Applying ReSisTrace in ovarian cancer cells perturbed with olaparib, carboplatin or natural killer (NK) cells reveals pre-resistant phenotypes defined by proteostatic and mRNA surveillance features, reflecting traits enriched in the upcoming subclonal selection. Finally, we leverage the obtained pre-resistance profiles to predict and validate small molecules driving cells to sensitive states prior to treatment. In summary, ReSisTrace resolves pre-existing transcriptional features of treatment vulnerability, facilitating both molecular patient stratification and discovery of synergistic pre-sensitizing therapies.

Taken together, inhibition of Chk1 by pristimerin has been observed to induce DNA repair deficiency, which may expand the application of olaparib in BRCA-proficient cancers harboring TP53 mutations. Thus, pristimerin can be combined for PARP inhibitor-based therapy.

Consistently, functional analysis of cell lines from the studied individuals revealed presence of residual FANCD2 ubiquitination and FANCD2 foci formation, better cell survival, and decreased late S/G2 accumulation in response to DNA interstrand crosslinking agent, indicating presence of residual activity of the FA repair pathway. Thus, the c.3624C>T variant is a hypomorphic allele, which contributes to delayed manifestation of FA disease phenotypes in individuals with at least one c.3624C>T allele.

Somatic and germline mutations in FANCC occur in an exceedingly small subset of clinically advanced RT but at similar rate to other cancers. RT with inactivated FANCC do not appear to have a different GA landscape from RT with wild-type FANCC. The high frequency of predicted germline status during somatic testing with FANCC alterations suggests the importance of further workup with confirmatory germline testing as it may affect counseling for other family members.

We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.

Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells.

In some settings, these changes can lead to increased sensitivity to immune checkpoint inhibitors (ICIs). In this review, we discuss the impact of specific DNA repair pathway dysfunction on immune contexture and ICI response in solid tumors.

This is the first study to investigate the distribution of Response Predictive Subtypes in ILC, which will be beneficial to optimize the treatment selection for patients with early-stage HR+/HER2- ILC. Though the percentage of ImPrint+ is lower in ILC, this study revealed a small subset of patients in ILC with potential response to Immunotherapy. Furthermore, these results underscore the heterogeneity of ILC tumors and generate further hypotheses to investigate the immune cell abundance in ILC compared to IDC and correlate immune cell abundance to ImPrint status.

Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.

In conclusion, in patients with a genetic predisposition, an unfavorable breast microbiota may be co-responsible for the onset of breast cancer. Prospectively, the ability to modulate the microbiota may have an impact on disease onset and progression in patients at high risk for breast cancer.

Our study shows that the KIF genes play an important pan-cancer role and may become a potential new target for a variety of tumor treatments in the future. Furthermore, KIF14, a key molecule in the KIF genes, can provide a new idea for the ccRCC treatment.

Meanwhile, histogram analysis of [F]FLT uptake indicated the potential translatability of imaging proliferation biomarkers. This study highlights the potential of combined trastuzumab and PARP inhibition in HER2+ breast cancer, while demonstrating a need for optimization of [F]FLT-PET quantification in heterogeneous models of HER2+ breast cancer.

EVI1 and PARP1 are robust prognostic biomarkers for favorable prognosis in HGSOC and imply further research with respect to their reciprocity.

We have previously reported that temozolomide (TMZ) is able to induce MMR defects and hypermutability leading to immunotherapy clinical benefit in the subset of CRCs characterized by inactivation of O6-methylguanine methyltransferase (MGMT)...Methods We studied the impact of commonly used cytotoxic agents such as 5-fluorouracil, irinotecan, oxaliplatin, cisplatin (CDDP) and TMZ on the immunogenomic features of CRC cells...The same effect is not observed when CDDP and TMZ are given as monotherapy or when CRC cells are primed with the 5-fluorouracil-oxaliplatin-irinotecan (FOLFOXIRI) triplet. Conclusions These results indicate that rational combinations of commonly used cytotoxic agents can be exploited to promote cancer cell hypermutability and immunogenicity, and have implications in the design of new chemo-immunotherapy approaches in CRC.

Our results suggest that sarcomatoid transformation exhibits adaption to hypoxia via a TGF-β/TEAD/EMT axis which is reversible by PRX3 inhibition.

Conclusion Survival in BRCA-mutants with HGSOC was associated with distinct mutational signatures, differential immune responses, somatic gene alterations, and differences in the extent of HRD. Integration of multi-omic data with clinical variables can enhance the accuracy of predictive models and inform alternative treatment options in patients predicted to have shorter survival.

Systemic treatment options are centered on the use of platinum-based combination chemotherapy, with the choice of cisplatin- or carboplatin-based regimens determined on the basis of criteria including performance status and renal function...Data on the use of adjuvant immunotherapy are currently contradictory, with disease-free survival demonstrated for adjuvant nivolumab, but not atezolizumab, and no overall survival benefit has yet been confirmed. The Nectin-4 directed antibody drug conjugate enfortumab vedotin is an established treatment option for patients previously treated with both chemotherapy and immunotherapy. The emerging therapeutic targets under evaluation include Trop-2 with sacituzumab govitecan, fibroblast growth factor receptors, HER2, and DNA repair deficiency in biomarker-selected patients. The development of properly validated predictive biomarkers has proven challenging for this disease and should be a central priority in the future development of treatment options. This review summarizes the available systemic treatment options in both palliative and curative disease settings, and highlights the available evidence and current limitations for making treatment recommendations.

Further consensus aligning germline with somatic molecular analysis in metastatic prostate cancer is required, including genomics scars, emergent immunohistochemistry or functional pre-screen imaging. With rapid advances in knowledge and technology in the field, continuous updating of guidelines to help the clinical management of these individuals, and well conducted studies to evaluate the benefits of genetic testing are needed.

We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

No abstract available

Targeted sequencing of genome-wide polymorphic SNP sites can be used to infer LOH events and subsequently diagnose HRD in ovarian tumors. The methods presented here are readily generalizable to other targeted gene oncology assays and could be adapted for HRD diagnosis in other tumor types.

Disease-specific trials, as well as reports of exceptional responses, may provide clues for novel approaches to this often hard-to-treat breast cancer. Strategies which harness newer research tools, such as large data and artificial intelligence hold the promise of overcoming historic barriers to the study of uncommon tumors and could markedly advance disease-specific understanding in MBC.

CDK12 is associated with tandem-duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the ROC curve=0.97). Our novel associations include mono- or biallelic LOF variants of ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy.

A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.

The emerging view is that in the kidney, DNA damage affects the local microenvironment by triggering a damage response and cell proliferation to replenish injured cells, as well as inducing systemic responses aimed at reducing exposure to genotoxic stress. The pathological consequences of DNA damage are therefore key to the nephrotoxicity of DNA-damaging agents and the kidney phenotypes observed in human DNA repair-deficiency disorders.

Mutational signature analysis suggests mutational processes that could give rise preferentially to splice mutations in each cancer type, with an enrichment of signatures related to clock-like processes and DNA repair deficiency. Altogether, this work sheds light on the causes and impact of cryptic splice mutations in cancer, and highlights the power of deep learning approaches to better annotate the functional consequences of mutations in oncology.

We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

Breast cancer cells cultured under hyperglycemia-like conditions acquire increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors that are cancer therapeutics.Key words: Breast cancer, diabetes, metabolome, transcriptome, metastasis, DNA repair, mutational signature, health disparity

However, the clinical use of ctDNA test in prostate cancer compared to blood and tissue testing are currently very limited. In this review, we summarize the current therapeutic indications in prostate cancer patients with DDR deficiency, the recommendation for germline and somatic-genomic testing in advanced PC and the advantages of the use liquid biopsy in clinical routine for mCRPC.

In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.

P2, N=1000, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | Recruiting --> Suspended

Our results showed that Mitoxantrone and Genistein were among drugs with high therapeutic effects that significantly reverted the gene expression changes caused by the disease (FDR adjusted p-values for prostate cancer =1.225e-4 and 8.195e-8, respectively) for patients with deficiencies in their homologous recombination (HR) pathways. The proposed multi-cancer treatment framework, suitable for patients whose cancers had common specific biomarkers, has the potential to identify promising drug candidates by enriching the study population through the integration of multiple cancers and targeting patients who respond poorly to organ-specific treatments.