RNASEH2B loss and PARP inhibition in advanced prostate cancer.

BACKGROUND: Clinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial. METHODS: Whole tumor biopsies from multiple cohorts of patients with advanced prostate cancer were interrogated using whole-exome sequencing (WES), RNA sequencing (bulk and single nucleus) and immunohistochemistry (IHC) for RNASEH2B and RB1. Biopsies from patients treated with olaparib in the TOPARP-A and TOPARP-B clinical trials were used to evaluate RNASEH2B clonal selection during olaparib treatment. RESULTS: Shallow co-deletion of RNASEH2B and adjacent RB1, co-located at chromosome 13q14, was common, deep co-deletion infrequent, and gene loss associated with lower mRNA expression. In castration-resistant PC (CRPC) biopsies, RNASEH2B and RB1 mRNA expression correlated, but single nucleus RNA sequencing indicated discordant loss of expression. IHC studies showed that loss of the two proteins often occurred independently, arguably due to stochastic second allele loss. Pre- and post-treatment metastatic CRPC (mCRPC) biopsy studies from BRCA1/2 wildtype tumors, treated on the TOPARP phase II trial, indicated that olaparib eradicates RNASEH2B-loss tumor subclones. CONCLUSION: PARP inhibition may benefit men suffering from mCRPC by eradicating tumor subclones with RNASEH2B loss. CLINICALTRIALS: gov NCT01682772FUNDING. AstraZeneca; Cancer Research UK; Medical Research Council; Cancer Research UK; Prostate Cancer UK; Movember Foundation; Prostate Cancer Foundation.

Presentations of Cutaneous Disease in Various Skin Pigmentations: Acne Vulgaris - Comedonal Acne.

Description Acne vulgaris is a common inflammatory skin condition of the pilosebaceous unit in adolescents and young adults and is primarily characterized by the presence of open and closed comedones. In patients of various skin pigmentations, skin-colored comedones may be difficult to appreciate and lead to incorrect or delayed diagnosis of acne. To aid in the identification of acne vulgaris in patients of various skin pigmentations, we present comedonal acne in different skin types and commonly encountered differential diagnoses. With its significant volume and burden of disease, acne vulgaris should be correctly identified in various skin pigmentations by primary care clinicians for the initiation of appropriate management.

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

PURPOSE: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease. EXPERIMENTAL DESIGN: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.

Changing trends in phase 1 oncology clinical trials.

The Ph1 oncology trial landscape is evolving in response to advances in understanding of cancer biology, novel drug discovery platforms, and therapeutic modalities. To uncover emerging trends in oncology drug development, we identified 7,061 solid tumour Ph1 trials (2009-2021) from clinicaltrials.gov to determine the numbers of trials commenced, therapeutic classes, combinations, tumour streams, and geographical distribution. Ph1 oncology trials increased by an average of 5.2 %/year. There was a significant relative increase in the number of immunotherapy studies and a significant relative decrease in trials containing chemotherapy. Between 2009 and 2021, multi-agent combination trials outnumbered single-agent trials and single-class trials outnumbered multimodal combination trials. The proportion conducted in the Asia-Pacific significantly increased. Multiregional trials decreased during the COVID-19 pandemic, reducing projected trial numbers in Asia-Pacific and Europe whilst increasing single-region trials in North America. Further study is required to track recovery post-pandemic, and the emergence of novel modalities (e.g. ADCs and cellular therapies).