Strategy In Oncology Research Articles

The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers.

Survival outcomes for patients with advanced ovarian cancer remain poor despite advances in chemotherapy and surgery. Platinum-based systemic chemotherapy can result in a response rate of up to 80%, but most patients will have recurrence and die from the disease. Recently, the DNA-repair-directed precision oncology strategy has generated hope for patients. The clinical use of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA germ-line-deficient and/or platinum-sensitive epithelial ovarian cancers has improved survival. However, the emergence of resistance is an ongoing clinical challenge. Here, we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in epithelial ovarian cancers.

The effectiveness of clinical guideline implementation strategies in oncology—a systematic review

ImportanceGuideline recommendations do not necessarily translate into changes in clinical practice behaviour or better patient outcomes.ObjectiveThis systematic review aims to identify recent clinical guideline implementation strategies in oncology and to determine their effect primarily on patient-relevant outcomes and secondarily on healthcare professionals' adherence.MethodsA systematic search of five electronic databases (PubMed, Web of Science, GIN, CENTRAL, CINAHL) was conducted on 16 december 2022. Randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) assessing the effectiveness of guideline implementation strategies on patient-relevant outcomes (overall survival, quality of life, adverse events) and healthcare professionals' adherence outcomes (screening, referral, prescribing, attitudes, knowledge) in the oncological setting were targeted. The Cochrane risk-of-bias tool and the ROBINS-I tool were used for assessing the risk of bias. Certainty in the evidence was evaluated according to GRADE recommendations. This review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42021268593.FindingsOf 1326 records identified, nine studies, five cluster RCTs and four controlled before-and after studies, were included in the narrative synthesis. All nine studies assess the effect of multi-component interventions in 3577 cancer patients and more than 450 oncologists, nurses and medical staff.Patient-levelEducational meetings combined with materials, opinion leaders, audit and feedback, a tailored intervention or academic detailing may have little to no effect on overall survival, quality of life and adverse events of cancer patients compared to no intervention, however, the evidence is either uncertain or very uncertain.Provider-levelMulti-component interventions may increase or slightly increase guideline adherence regarding screening, referral and prescribing behaviour of healthcare professionals according to guidelines, but the certainty in evidence is low. The interventions may have little to no effect on attitudes and knowledge of healthcare professionals, still, the evidence is very uncertain.Conclusions and relevanceKnowledge and skill accumulation through team-oriented or online educational training and dissemination of materials embedded in multi-component interventions seem to be the most frequently researched guideline implementation strategies in oncology recently. This systematic review provides an overview of recent guideline implementation strategies in oncology, encourages future implementation research in this area and informs policymakers and professional organisations on the development and adoption of implementation strategies.

Leveraging Advanced In Silico Techniques in Early Drug Discovery: A Study of Potent Small-Molecule YAP-TEAD PPI Disruptors.

Disruption of the YAP-TEAD protein-protein interaction is an attractive therapeutic strategy in oncology to suppress tumor progression and cancer metastasis. YAP binds to TEAD at a large flat binding interface (∼3500 Å2) devoid of a well-defined druggable pocket, so it has been difficult to design low-molecular-weight compounds to abrogate this protein-protein interaction directly. Recently, work by Furet and coworkers (ChemMedChem 2022, DOI: 10.1002/cmdc.202200303) reported the discovery of the first class of small molecules able to efficiently disrupt the transcriptional activity of TEAD by binding to a specific interaction site of the YAP-TEAD binding interface. Using high-throughput in silico docking, they identified a virtual screening hit from a hot spot derived from their previously rationally designed peptidic inhibitor. Structure-based drug design efforts led to the optimization of the hit compound into a potent lead candidate. Given advances in rapid high-throughput screening and rational approaches to peptidic ligand discovery for challenging targets, we analyzed the pharmacophore features involved in transferring from the peptidic to small-molecule inhibitor that could enable small-molecule discovery for such targets. Here, we show retrospectively that pharmacophore analysis augmented by solvation analysis of molecular dynamics trajectories can guide the designs, while binding free energy calculations provide greater insight into the binding conformation and energetics accompanying the association event. The computed binding free energy estimates agree well with experimental findings and offer useful insight into structural determinants that influence ligand binding to the TEAD interaction surface, even for such a shallow binding site. Taken together, our results demonstrates the utility of advanced in silico methods in structure-based design efforts for difficult-to-drug targets such as the YAP-TEAD transcription factor complex.

Unravelling the clinicopathological and functional significance of replication protein A (RPA) heterotrimeric complex in breast cancers

Replication Protein A (RPA), a heterotrimeric complex consisting of RPA1, 2, and 3 subunits, is a single-stranded DNA (ssDNA)-binding protein that is critically involved in replication, checkpoint regulation and DNA repair. Here we have evaluated RPA in 776 pure ductal carcinomas in situ (DCIS), 239 DCIS that co-exist with invasive breast cancer (IBC), 50 normal breast tissue and 4221 IBC. Transcriptomic [METABRIC cohort (n = 1980)] and genomic [TCGA cohort (n = 1090)] evaluations were completed. Preclinically, RPA deficient cells were tested for cisplatin sensitivity and Olaparib induced synthetic lethality. Low RPA linked to aggressive DCIS, aggressive IBC, and shorter survival outcomes. At the transcriptomic level, low RPA tumours overexpress pseudogene/lncRNA as well as genes involved in chemical carcinogenesis, and drug metabolism. Low RPA remains linked with poor outcome. RPA deficient cells are sensitive to cisplatin and Olaparib induced synthetic lethality. We conclude that RPA directed precision oncology strategy is feasible in breast cancers.

Design and Biochemical Characterization of Peptidic Inhibitors of the Myb/p300 Interaction.

The Myb transcription factor is involved in the proliferation of hematopoietic cells, and deregulation of its expression can lead to cancers such as leukemia. Myb interacts with various proteins, including the histone acetyltransferases p300 and CBP. Myb binds to a small domain of p300, the KIX domain (p300KIX), and inhibiting this interaction is a potential new drug discovery strategy in oncology. The available structures show that Myb binds to a very shallow pocket of the KIX domain, indicating that it might be challenging to identify inhibitors of this interaction. Here, we report the design of Myb-derived peptides which interact with p300KIX. We show that by mutating only two Myb residues that bind in or near a hotspot at the surface of p300KIX, it is possible to obtain single-digit nanomolar peptidic inhibitors of the Myb/p300KIX interaction that bind 400-fold tighter to p300KIX than wildtype Myb. These findings suggest that it might also be possible to design potent low molecular-weight compounds to disrupt the Myb/p300KIX interaction.

Chimeric antigen receptor-T cells are effective against CEACAM5 expressing non-small cell lung cancer cells resistant to antibody-drug conjugates.

Chimeric antigen receptor-T (CAR-T) cells and antibody-drug conjugates (ADCs) are promising therapeutic strategies in oncology. The carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is overexpressed in tumors including non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC), and is an attractive target for therapies based on CAR-T cell or/and ADCs. We previously developed a highly specific antibody-based CAR-T cells targeting CEACAM5 and the tumoricidal effect of CAR-T cells was proved against neuro-endocrine prostate cancer (NEPC) cells expressing CEACAM5. Here, we compare the anti-tumor efficacy of our CAR-T cells with that of an anti-CEACAM5 ADC being clinically evaluated against NSCLC. Our anti-CEACAM5 CAR-T cells showed cytotoxicity in a CEACAM5 surface concentration dependent manner and reduced tumor growth in both ADC-responsive and -non-responsive CEACAM5-expressing NSCLC cells in vitro and in vivo. In contrast, the ADC exhibited cytotoxicity independent on the CEACAM5 cell surface concentration. Even though clinical translation of CEACAM5 targeting CAR-T cell therapies is still in preclinical stage, our CAR-T cell approach could provide a potential therapeutic strategy for CEACAM5-positive cancer patients with resistance to ADCs.

Evaluating the Histologic Grade of Digital Squamous Cell Carcinomas in Dogs and Copy Number Variation of KIT Ligand—A Correlation Study

Dark-haired dogs are predisposed to the development of digital squamous cell carcinoma (DSCC). This may potentially suggest an underlying genetic predisposition not yet completely elucidated. Some authors have suggested a potential correlation between the number of copies KIT Ligand (KITLG) and the predisposition of dogs to DSCC, containing a higher number of copies in those affected by the neoplasm. In this study, the aim was to evaluate a potential correlation between the number of copies of the KITLG and the histological grade of malignancy in dogs with DSCC. For this, 72 paraffin-embedded DSCCs with paired whole blood samples of 70 different dogs were included and grouped according to their haircoat color as follow: Group 0/unknown haircoat color (n = 11); Group 1.a/black non-Schnauzers (n = 15); group 1.b/black Schnauzers (n = 33); group 1.c/black and tan dogs (n = 7); group 2/tan animals (n = 4). The DSCCs were histologically graded. Additionally, KITLG Copy Number Variation (CNV) was determined by ddPCR. A significant correlation was observed between KITLG copy number and the histological grade and score value. This finding may suggest a possible factor for the development of canine DSCC, thus potentially having an impact on personalized veterinary oncological strategies and breeding programs.

Soft Tissue Sarcomas in Octogenarian Patients: Are Treatment Options and Oncological Outcomes Different? A SEER Retrospective Study

AimsAs the US population continues to age, oncological strategies and outcomes for soft tissue sarcomas (STSs) should continue to be examined for varying age groups. The aim of this study was analyse and compare treatment strategies and oncological outcomes for octogenarian patients with STSs. Materials and methodsData from the Surveillance, Epidemiology and End Results (SEER) national database were used. Varying treatment modalities were studied when utilised for specific tumour staging with respect to the eighth edition of the American Joint Committee on Cancer. ResultsIn total, 24 666 patients were included for analysis, where 3341 (14%) were 80 years old or older. The octogenarian group was diagnosed with more advanced disease (stages II–IV), relative to their younger counterparts (85% versus 75%, P < 0.001). However, a smaller proportion of the older patients underwent surgical resection (74% versus 86%, P < 0.001). Likewise, the octogenarians received less chemotherapy (4% versus 21%, P < 0.001) and radiotherapy (29% versus 42%, P = 0.010). Surgical resection and chemotherapy significantly improved overall survival for those older patients with stage II STS, whereas surgical resection and radiotherapy improved mortality in this cohort with both stage III and IV STS. Overall survival at 1 and 5 years of follow-up was lower within the octogenarian group compared with the younger group (1 year: 68% versus 88%, P < 0.001 and 5 years: 7% versus 58%, P < 0.001). ConclusionsOctogenarian patients, in most cases, are diagnosed with stage III or metastatic disease. Surgical resection of the primary tumour was beneficial in both age cohorts, with radiotherapy correlating to better overall survival when used in those patients with higher stage STS. Chemotherapy was associated with better mortality in the younger cohort with respect to tumour stage. The octogenarian overall survival at 1 and 5 years was lower than for younger patients.

Prognosis, immune microenvironment, and personalized treatment prediction in Rho GTPase-activating protein 4-mutant cervical cancer: Computer strategies for precision oncology

AimsCervical cancer with different mutations is associated with specific genomic differences.We developed a new mutation prediction model of the ARHGAP4 gene for cervical cancer. Main methodsWe conducted a panoramic analysis of CESC mutations based on The Cancer Genome Atlas-Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) database. We made copy number variation analysis and correlation analysis of somatic mutations and tumor mutation load fraction. Then we established a prediction model of ARHGAP4 mutation, screened related genes based on the risk scores, calculated the correlation between the risk score and immune microenvironment, and analyzed drug sensitivity. Key findingsThe prediction model of ARHGAP4 mutation based on mRNA expression is closely related to the survival rate of cervical cancer patients and to the effect of immunotherapy. The prediction model is also related to the infiltration of immune cells and human leukocyte antigen family expression in the immune microenvironment. After computational analysis, three drugs (cytarabine, docetaxel, imatinib) were identified as potential agents for the ARHGAP4 mutation high-risk group, and two drugs (erlotinib, methotrexate) were shown to have therapeutic significance for patients in the low-risk group. The expression of ARHGAP4 was higher in cervical cancer tissues. The proliferation ability of HeLa and SiHa cells decreased after ARHGAP4 knockdown. SignificanceThis study provides not only a new approach for the prediction of the response of the cervical cancer patients to targeted drug therapy but also a new strategy for combining risk stratification with precision treatment.

Recent Progress in Immunotherapy for Gastric Cancer

Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Under the standard of care, patients with advanced GC (AGC) have a median survival time of approximately 12-15 months. With the emergence of immunotherapy as a key therapeutic strategy in medical oncology, relevant changes are expected in the systemic treatment of GC. In the phase III ATTRACTION-2 trial, nivolumab, a monoclonal anti-programmed cell death 1 (PD-1) antibody, as a third- or later-line treatment improved overall survival (OS) compared with placebo in patients with AGC. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment improved OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the global phase III CheckMate-649 study. Another anti-PD-1 antibody, pembrolizumab, in combination with trastuzumab and cytotoxic chemotherapy as a first-line treatment, significantly improved the overall response rate in patients with HER2-positive AGC. Therefore, immune checkpoint inhibitors (ICIs) are essential components of the current treatment of GC. Subsequent treatments after ICI combination therapy, such as ICI rechallenge or combination therapy with agents having other modes of action, are being actively investigated to date. On the basis of the success of immunotherapy in the treatment of AGC, various clinical trials are underway to apply this therapeutic strategy in the perioperative and postoperative settings for patients with early GC. This review describes recent progress in immunotherapy and potential immunotherapy biomarkers for GC.

Wykorzystanie potencjału naukowo-badawczego i leczniczego oraz kondycja finansowa Narodowego Instytutu Onkologii im. Marii Skłodowskiej-Curie w latach 2017–2021

Purpose – The study concerns the National Institute of Oncology, which is the largest medical research institute in Poland. It presents the development of the institution and evaluates the scientific, research and treatment activities as well as the financial situation of the above‑mentioned institutions. Research method – The article is a case study. The method of examining documents and data contained in the annual activity reports of the Director of the NIO and its financial statements for the years 2017–2021 has been used. In evaluation the Institute, the indicators for public healthcare entities included in the regulation of the Minister of Health has been applied. Results – The National Institute of Oncology conducts extensive research and develops innovative treatment methods that are practically used in the diagnosis and treatment of cancer. He actively participates in a task of exceptional importance for improving public health in Poland, i.e. the National Oncology Strategy. The difficult financial situation of the entity is gradually improving. Originality/value/implications/recommendations – The issue of medical research institutes is not handled in the literature on public health or public finance. Therefore, this publication fills the existing gap to some extent and is part of the series of articles devoted to the above‑mentioned issues, implemented by the authors. entities.

Integrated analysis of transcriptomics and metabolomics demonstrates the role of ceremide phosphoethanolamines and phosphatidylcholines in conferring resistance to first- line chemotherapy in patients with oesophageal adenocarcinoma

Introduction: Chemotherapy resistance is a major obstacle in the treatment of oesophageal adenocarcinoma patients (OAC). There is an unmet need for personalised tools that identify chemoresistant patients, so effective oncological strategies can be implemented.

Replication stress drives chromosomal instability in fibroblasts of childhood cancer survivors with second primary neoplasms

New development and optimization of oncologic strategies are steadily increasing the number of long-term cancer survivors being at risk of developing second primary neoplasms (SPNs) as a late consequence of genotoxic cancer therapies with the highest risk among former childhood cancer patients. Since risk factors and predictive biomarkers for therapy-associated SPN remain unknown, we examined the sensitivity to mild replication stress as a driver of genomic instability and carcinogenesis in fibroblasts from 23 long-term survivors of a pediatric first primary neoplasm (FPN), 22 patients with the same FPN and a subsequent SPN, and 22 controls with no neoplasm (NN) using the cytokinesis-block micronucleus (CBMN) assay. Mild replication stress was induced with the DNA-polymerase inhibitor aphidicolin (APH). Fibroblasts from patients with the DNA repair deficiency syndromes Bloom, Seckel, and Fanconi anemia served as positive controls and for validation of the CBMN assay supplemented by analysis of chromosomal aberrations, DNA repair foci (γH2AX/53BP1), and cell cycle regulation. APH treatment resulted in G2/M arrest and underestimation of cytogenetic damage beyond G2, which could be overcome by inhibition of Chk1. Basal micronuclei were significantly increased in DNA repair deficiency syndromes but comparable between NN, FPN, and SPN donors. After APH-induced replication stress, the average yield of micronuclei was significantly elevated in SPN donors compared to FPN (p = 0.013) as well as NN (p = 0.03) donors but substantially lower than for DNA repair deficiency syndromes. Our findings suggest that mild impairment of the response to replication stress induced by genotoxic impacts of DNA-damaging cancer therapies promotes genomic instability in a subset of long-term cancer survivors and may drive the development of an SPN. Our study provides a basis for detailed mechanistic studies as well as predictive bioassays for clinical surveillance, to identify cancer patients at high risk for SPNs at first diagnosis.

Evolving DNA repair synthetic lethality targets in cancer.

DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. Impaired DNA repair capacity is an important risk factor for cancer development. On the other hand, up-regulation of DDR mechanisms is a feature of cancer chemotherapy and radiotherapy resistance. Advances in our understanding of DDR and its complex role in cancer has led to several translational DNA repair-targeted investigations culminating in clinically viable precision oncology strategy using poly(ADP-ribose) polymerase (PARP) inhibitors in breast, ovarian, pancreatic, and prostate cancers. While PARP directed synthetic lethality has improved outcomes for many patients, the lack of sustained clinical response and the development of resistance pose significant clinical challenges. Therefore, the search for additional DDR-directed drug targets and novel synthetic lethality approaches is highly desirable and is an area of intense preclinical and clinical investigation. Here, we provide an overview of the mammalian DNA repair pathways and then focus on current state of PARP inhibitors (PARPi) and other emerging DNA repair inhibitors for synthetic lethality in cancer.

Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

Abstract IA009: Tumor organoids of multi-metastatic colorectal cancer: From research tools to treatment decision tools

Abstract Most patients with colorectal cancer (CRC) do not have an “actionable” target based on molecular tumor profiling. Ex vivo drug sensitivity testing of tumor organoids holds promise as a complementary approach in precision oncology. We have established a pre-clinical pharmacogenomics platform for CRC at Oslo University Hospital. A living biobank of 208 organoids of distinct liver lesions from 100 patients treated by hepatic resection for metastatic CRC was generated in the observational phase of the project. Sensitivity testing of custom drug libraries (n=40-47 drugs) and molecular profiling (targeted DNA sequencing, RNA sequencing, multiplex immunohistochemistry) indicated that the organoids recapitulate well-known pharmacogenomic associations, phenotypic tumor features, and clinical treatment responses (n=35 patients published (ref 1,2)). Evaluation of multiple lesions (n=2-6) per patient suggested diversity among patients in the level of inter-metastatic heterogeneity of drug sensitivities, supporting the need for multi-tumor evaluations in a clinical setting. A collection of CRC cell lines (n=107) was screened for sensitivity to more than 500 drugs and this suggested a molecular basis for response to selected targeted agents, including to PARP inhibition in a small subset of the cell lines (ref 3). Combination screens suggested possibility to overcome acquired resistance to dual BRAF and EGFR blockade in BRAFV600E cells (unpublished data). The living biobank serves as a reference for drug nominations in an ongoing phase II umbrella trial of pharmacogenomics-guided treatment in patients with metastatic CRC (EVIDENT; EU Clinical Trials Register no. 2020-003395-41). Several ad hoc patient cases have been screened as a pilot for the trial, and data of clinical benefit from this functional precision oncology strategy will be presented.

Predictors of Survival in Elderly Patients with Metastatic Colon Cancer: A Population-Based Cohort Study.

Oncological strategies in the elderly population are debated. The objective of this study was to determine the predictive factors of survival in patients aged 80 years and older with metastatic colon cancer. Data from four digestive tumour registry databases were used in this analysis. This population-based retrospective study included 1115 patients aged 80 years and older with stage IV colon adenocarcinoma diagnosed between 2007 and 2016. Cox regression was used to assess the impact of different prognostic factors. Age was significantly correlated with the surgical treatment (p < 0.001) but not with overall survival. Patients with a low comorbidity burden had better survival than patients with higher comorbidities scores (9.4 (0−123) versus 7.9 (0−115) months) (p = 0.03). Surgery was more common for proximal colon cancer (p < 0.001), but the location of the primary lesion was not correlated with improved survival (p = 0.07). Patients with lung metastases had a better prognosis than those with liver metastases (HR 0.56 95% CI 0.40, 0.77 p < 0.001); multiple organ involvement had the worst survival (HR 1.32 95% CI 1.15, 1.51 p < 0.001). Chemotherapy was associated with improved survival for both operated (HR 0.45 95% CI 0.35, 0.58 p < 0.001) and non-operated patients (HR 0.41 95% CI 0.34, 0.50 p < 0.001). The majority of patients receiving adjuvant treatment had a low comorbidity burden. In our study, the location of metastases but not the primary tumor location had an impact on overall survival. Low comorbidity burden, curative surgery, and chemotherapy had a significant advantage for elderly patients with metastatic colon cancer.

94 (PB084) - Novel inhibitors of the luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) durably eradicate tumors in urothelial cancer (UC) animal models

Background: Small molecule targeting of cell lineage-defining transcription factors is a demonstrated and effective therapeutic strategy in oncology, exemplified by estrogen receptor (ER) agents in luminal breast cancer. Two-thirds of advanced UC is classified as luminal and overexpression of PPARG is characteristic of this molecular subtype. Currently, there is a poor understanding of how recurrent missense mutations in PPARG and its obligate heterodimer retinoid X receptor alpha (RXRA) impact PPARG function; previous tool compounds designed to inhibit PPARG have minimal phenotypic activity in UC cell lines. Material and Methods: The PPARG inhibitor FTX-6746 was evaluated in UC cell lines including UMUC9 (PPARG amplification) and HT1197 (RXRA-S427F hotspot mutation), which activate PPARG by different genetic mechanisms. In vitro analyses included clonogenic growth assays and assessment of target gene modulation after treatment. in vivo studies were performed in NCG or Balb/C nude mice with oral administration of FTX-6746 at doses indicated below. Results: Our biochemical studies indicate that patient-derived missense mutations in PPARG and RXRA bias an active conformation of PPARG, mimicking an agonist-bound state. Addressing the limitations of previous tool compounds, we discovered novel inhibitors that drive a powerful repressive conformation of PPARG with high specificity (>100X selective over PPARA/ PPARD). This results in robust PPARG target gene silencing in cells (IC50 = 5 nM), and in vitro growth inhibition preferentially observed in cell lines with activated PPARG signaling. Tumor growth inhibition or regression was observed in two xenograft models of UC at well-tolerated oral doses with no tumor regrowth upon cessation of treatment. Treatment of UMUC9 xenograft tumors with 3, 10, 30 and 60 mg/kg twice daily of FTX-6746 resulted in up to 80% target gene suppression in tumor tissue at day 2 and up to >100% tumor growth inhibition at day 21. Similar efficacy was observed in HT1197 xenograft studies treated with 30 and 60 mg/kg twice daily of FTX-6746, with >45% target gene suppression at day 2 and 85–112% tumor growth inhibition at day 42.Tabled 1ModelDose (mg/kg)Schedule%Tumor Growth Inhibition%Target Gene Suppression (D2)UMUC93BID*205916UMUC910BID*2070NDUMUC930BID*208373UMUC930BID*2110580UMUC960BID*21108NDHT119730BID*428546HT119760BID*4211259 Open table in a new tab Conclusions: These collective results suggest that PPARG is a lineage-defining transcription factor in UC and small molecule PPARG inhibition will be an effective therapy for patients with advanced urothelial cancer harboring the luminal subtype. Conflict of interest: Ownership: All authors are shareholders in Flare Therapeutics.

Homologous Recombination Deficiency as an Ovarian Cancer Biomarker in a Real-World Cohort: Validation of Decentralized Genomic Profiling

The diagnostic evaluation of homologous recombination deficiency (HRD) is central to define targeted therapy strategies for patients with ovarian carcinoma. We evaluated HRD in 514 ovarian carcinoma samples by next-generation sequencing of DNA libraries, including BRCA1/BRCA2 and 26,523 single-nucleotide polymorphisms using the standardized Myriad HRD assay, with the predefined cut point of ≥42 for a positive genomic instability score (GIS). All samples were measured in the central Myriad laboratory and in an academic molecular pathology laboratory. A positive GIS was detected in 196 (38.1%) of tumors, whereas 318 (61.9%) were GIS negative. Combining GIS and BRCA mutations, a total of 200 (38.9%) of the 514 tumors were HRD positive. A positive GIS was significantly associated with high-grade serous histology (P<0.000001), grade 3 tumors (P=0.001), and patient age <60 years (P=0.0003). The concordance between both laboratories for the GIS status was 96.9% (P<0.000001), with a sensitivity of 94.6% and a specificity of 98.4%. Concordance for HRD status was 97.1% (499 of 514 tumors). The percentage of HRD-positive tumors in our real-life cohort was similar to the proportion observed in the recently published PAOLA-1 trial, with high concordance between central and local laboratories. Our results support introduction of the standardized HRD assay in academic molecular pathology laboratories, thus broadening access to personalized oncology strategies for patients with ovarian cancer worldwide.

Intracellular radar: Understanding γδ T cell immune surveillance and implications for clinical strategies in oncology.

T cells play a key role in anticancer immunity, with responses mediated through a diversity of αβ or γδ T cell receptors. Although αβ and γδ T cells stem from common thymic precursors, the development and subsequent biological roles of these two subsets differ considerably. γδ T cells are an unconventional T cell subset, uniquely poised between the adaptive and innate immune systems, that possess the ability to recognize intracellular disturbances and non-peptide-based antigens to eliminate tumors. These distinctive features of γδ T cells have led to recent interest in developing γδ-inspired therapies for treating cancer patients. In this minireview, we explore the biology of γδ T cells, including how the γδ T cell immune surveillance system can detect intracellular disturbances, and propose a framework to understand the γδ T cell-inspired therapeutic strategies entering the clinic today.