DDR

We tested whether this HR dysfunction could indeed be exploited using PARP inhibition and found that talazoparib treatment produced a durable growth suppression in vitro and in multiple ILC xenografts in vivo...ILC are rarely associated with biomarkers of HR deficiency, and as such patients are rarely eligible for treatment with PARP inhibitors. Our work suggests ILC present with a previously unappreciated form of HR dysfunction, linked to ILC-specific genomic activity of ER and MDC1, which imparts sensitivity to PARP inhibition.

Cell line SNMF signatures recapitulated tumour-derived COSMIC signatures and predicted DDR pathway deficiency of TCGA tumours with high recall, suggesting that SNMF-like models can leverage libraries of induced DDR deficiencies to decipher intricate DDR signatures underlying patient tumours. https://github.com/joanagoncalveslab/SNMF .

Subsequently, this paper presents several promising strategies to tackle PARPi resistance, including but not limited to: structural modifications of PARPi, deployment of gene editing systems, implementation of "membrane lipid therapy," and modulation of cellular metabolism in tumors. By integrating these strategies, this research will provide comprehensive approaches to overcome the resistance of PARPi in cancer treatment and offer guidance for future research and clinical practice.

In addition, proanthocyanidins reduced the elevated oxidative stress and recovered the disrupted DNA repair mechanism in the autistic animals by decreasing the expressions of Gadd45a and Parp1 levels and enhancing the expressions of Ogg1, P53, and Xrcc1 genes. This indicates that proanthocyanidins have significant potential as a new therapeutic strategy for alleviating autistic features.

There are now ongoing efforts to combine DDR inhibitors with the newest bladder cancer therapies, such as antibody-drug conjugates. This review highlights the most recent advances in targeting DNA repair deficiency in the evolving treatment landscape of bladder cancer.

P1/2, N=102, Active, not recruiting, University of Michigan Rogel Cancer Center | Recruiting --> Active, not recruiting

I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .

This ongoing research is essential for improving the management and outcomes of TNBC, which is a challenging and heterogeneous form of breast cancer. The findings of this research have practical implications for refining treatment strategies, particularly in selecting appropriate systemic therapies and integrating traditional treatment modalities like surgery and radiotherapy into comprehensive care plans for TNBC patients.

The digital cell counts demonstrated how immune markers are coexpressed in the TIME when considering TNBC molecular subtypes and DNA repair deficiency, and how combination of immune status with DNA repair deficiency status can improve the prognostic stratification in chemotherapy treated patients. These results underscore the value and potential of integrating TIME and specific tumour intrinsic alterations/phenotypes for the molecular understanding of TNBC.

In addition, low expression of the xrcc4 gene has been associated with better overall survival probability (p=0.032). Our results, even though retrospective and in a small number of patients, highlight the importance of DSBs repair and propose a potential therapeutic target for this type of sarcoma.

Overall, increasing the tumor mutational burden by PARP1 degradation and mitochondrial deregulation makes CML suitable for immunotherapy.

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.