olaparib (myChoice CDx)

Optimization of a Series of Novel 1H-Pyrrolo[3,2-c]pyridine-Based USP1 Inhibitors with Potent In Vivo Antitumor Activity.

Yang Tao T, Cui Xue X, Li Qingyan Q, Teng Yaxin Y et al.

USP1, a deubiquitinating enzyme critical for DNA damage repair, represents a promising therapeutic target for cancers. In this study, we employed scaffold hopping to design and synthesize a series of 1H-pyrrolo[3,2-c]pyridine-based USP1 inhibitors. Among these, the lead compound 38a displayed robust enzymatic and cellular potencies. 38a dose-dependently induced Ub-PCNA accumulation, triggered cell cycle arrest, and potently suppressed cell viability. Additionally, 38a synergized with olaparib in MDA-MB-463 cells. Uniquely, 38a effectively induced c-MYC downregulation. In vivo studies confirmed 38a's favorable oral bioavailability. In the MDA-MB-436 xenograft model, the combination of 38a with olaparib exerted potent antitumor efficacy, with a tumor inhibition rate of 80.7%, and the antitumor activity of 38a stemmed from USP1 inhibition. Furthermore, in the DLBCL PDX model with high c-MYC expression, 38a demonstrated efficacy comparable to standard first-line therapies. Preliminary safety evaluation confirmed the safety profile of 38a. Taken together, 38a is a highly promising antitumor lead compound with great translational potential.

Individualized pharmacotherapy: background and development.

Jørgensen Jan Trøst JT, Westergaard Niels N

Most drug prescriptions are still based on empiricism and not on solid biological data, which often results in considerable patient variability and, sometimes, low patient benefits. Although variability in patient response to pharmacotherapy has long been recognized, only in recent decades have new molecule analytical methods provided insight into some of the causes, which are often related to somatic or germline genetic variations. Based on this insight, different predictive biomarker tests have been developed to optimize and individualize pharmacotherapy. These biomarker tests are classified as companion diagnostic (CDx) or pharmacogenetic (PGx) tests. In both the United States and Europe, CDx and PGx information is part of the regulatory drug labeling and is included in the Prescribing Information for the individual drugs and biologics. In the United States, this type of information is found in the labeling of more than 400 regulatory-approved drugs and biological products. Despite these measures and the documented clinical utility of CDx and PGx testing, clinical implementation is lagging, especially with regard to PGx. There are various reasons for the lack of testing, such as insufficient education and awareness among healthcare professionals, inadequate access to biomarker testing, regulatory hurdles, and insufficient reimbursements. Although progress has been made in recent years, further efforts are needed to fully realize the potential of individualized pharmacotherapy by integrating the use of predictive biomarkers into routine clinical practice.

Family-based analyses show how children's genetics shape key traits.

Uptake of germline testing for Lynch Syndrome in patients with deficient mismatch repair/ microsatellite-high colorectal cancer in the public hospital system in South Australia.

Vembar Preethi P, Dow Eryn E

Lynch syndrome (LS) accounts for approximately 4% of colorectal cancer (CRC) cases and arises from pathogenic variants in mismatch repair (MMR) genes. Australian guidelines recommend universal MMR or microsatellite instability (MSI) screening in all CRC patients; however, real-world uptake remains variable. This study evaluated rates of MMR/MSI screening, germline testing, and genetics referrals across two major public hospitals in South Australia. A retrospective review of 1775 patients discussed at colorectal multidisciplinary team meetings in the Royal Adelaide and Queen Elizabeth hospitals between January 2021 and December 2023 was conducted to identify rates of MMR/MSI screening and subsequent referral of eligible patients to genetics. Of the 1129 colorectal cancer cases identified, MMR/MSI testing was performed in 93.2% (1052/1129), with deficiency detected in 12.5% (131/1052). Of these, 37% (49/131) were eligible for genetics referral after exclusion of somatic causes. Among eligible patients, 73.5% (36/49) were referred, and 43% (21/49) underwent germline testing. LS was confirmed in 12 patients (9% of deficient MMR CRC), while 9 patients (6.9%) were classified as having Lynch-like syndrome. Despite high screening rates, gaps remain in genetics referral and testing. Barriers included lack of reflex testing, loss to follow-up, and patient refusal. Targeted system-level interventions and improved genomic education are needed to enhance adherence to guidelines and optimise patient outcomes.