Hannes Vogel

Background: Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer that leads to severe neurologic symptoms and poor prognosis. Current treatment options, including radiation and intrathecal chemotherapy, offer limited efficacy and are associated with significant toxicity. Generally, systemic therapy in LMD poorly penetrates the blood-brain barrier (BBB). Leveraging the L-type amino acid transporter 1 (LAT1) represents a unique therapeutic strategy, as LAT1 facilitates transport of medications across the BBB, and is also highly expressed in metastatic cancer cells. QBS72S is a first-in-class BBB-penetrant bifunctional molecule targeting overexpression of LAT1 to selectively eliminate cancer cells. It has shown preclinical efficacy in a mouse model of breast cancer LMD. Methods: This Phase 2a, single-arm, open-label clinical trial (NCT05305365) investigated the safety, cerebrospinal fluid (CSF) concentration, pharmacokinetics, and preliminary efficacy of QBS72S in participants with breast cancer brain metastases. Secondary endpoints included progression-free survival, overall survival, and duration of response. Correlative analyses included LAT1 immunohistochemistry and CSF cell-free RNA sequencing. Results: In this analysis, we report results from breast cancer participants with LMD (n = 10) treated with QBS72S. QBS72S was reliably detected in CSF, adequately tolerated, and two participants exhibited long-term radiographic stability or improvement lasting 6-7 months. Conclusions: These early findings support further investigation of QBS72S as a targeted therapy for LMD, addressing an urgent unmet need in metastatic breast cancer.

Identification of 4 groups within TCGA PAAD data.

Phenotypes in acinar cell of origin Arf knockout and double Arf and Trp53 knockout mouse cohorts

Analysis of PDAC development from adult mouse acinar cells across different Arf and Trp53 genotypes

CDKN2A alterations are common in mouse KTC PDACs.

Expression of Ink4a and a p53 tumor suppression-associated gene (TSAG) signature

Transcriptome analysis of PDACs from KTC, KTC;Trp53fl/fl, KTC;Arffl/fl and KTC;Trp53fl/fl; Arffl/fl mice

Summary of types of mutations found in CDKN2AARF and CDKN2AINK4A in Group 1 to 4 PDACs.

The CDKN2A locus, which is frequently deleted in pancreatic ductal adenocarcinoma (PDAC), encodes two tumor suppressors, ARF and INK4A, that may influence tumorigenesis through distinct mechanisms. Distinguishing their individual contributions to cancer could help improve the understanding of PDAC pathogenesis and potentially uncover targetable vulnerabilities. Moreover, whereas ARF is known to enhance p53 function, defining its p53-independent activities could elucidate new processes that drive PDAC development. In this study, we sought to understand ARF function in PDAC suppression. Analysis of gene expression and mutational patterns in human PDAC TCGA data indicated that CDKN2AARF and CDKN2AINK4A are commonly both affected by point mutations and/or deletions, suggesting that their combined inactivation contributes to PDAC development. In genetically engineered mouse models, Arf inactivation accelerated KRASG12D-driven PDAC development, both in the presence and absence of Trp53, demonstrating that ARF is a PDAC-suppressor and can act in a p53-independent manner. Transcriptomic analyses of PDACs supported a p53-independent role for ARF, with ARF deficiency promoting extracellular matrix, collagen synthesis/assembly, and epithelial–mesenchymal transition gene expression programs. Accordingly, ARF-deficient PDACs displayed extensive remodeling of the tumor microenvironment (TME), associated with collagen deposition, increased tissue stiffness, and higher fibroblast content—hallmarks of aggressive and treatment-resistant PDAC stroma. Together, this study shows how ARF deficiency associated with CDKN2A inactivation sculpts the PDAC TME in a p53-independent fashion. Given the central role of the TME in PDAC progression and therapeutic resistance, these findings may provide insight critical for improving therapeutic interventions for PDAC.Significance:ARF deficiency induced by CDKN2AARF alterations promotes remodeling of the pancreatic cancer microenvironment, which could provide a genotype-specific therapeutic vulnerability to improve outcomes of pancreatic cancer patients.See related commentary by Destefanis and Mulvaney, p. 3101

The CDKN2A locus, which is frequently deleted in pancreatic ductal adenocarcinoma (PDAC), encodes two tumor suppressors, ARF and INK4A, that may influence tumorigenesis through distinct mechanisms. Distinguishing their individual contributions to cancer could help improve the understanding of PDAC pathogenesis and potentially uncover targetable vulnerabilities. Moreover, whereas ARF is known to enhance p53 function, defining its p53-independent activities could elucidate new processes that drive PDAC development. In this study, we sought to understand ARF function in PDAC suppression. Analysis of gene expression and mutational patterns in human PDAC TCGA data indicated that CDKN2AARF and CDKN2AINK4A are commonly both affected by point mutations and/or deletions, suggesting that their combined inactivation contributes to PDAC development. In genetically engineered mouse models, Arf inactivation accelerated KRASG12D-driven PDAC development, both in the presence and absence of Trp53, demonstrating that ARF is a PDAC-suppressor and can act in a p53-independent manner. Transcriptomic analyses of PDACs supported a p53-independent role for ARF, with ARF deficiency promoting extracellular matrix, collagen synthesis/assembly, and epithelial–mesenchymal transition gene expression programs. Accordingly, ARF-deficient PDACs displayed extensive remodeling of the tumor microenvironment (TME), associated with collagen deposition, increased tissue stiffness, and higher fibroblast content—hallmarks of aggressive and treatment-resistant PDAC stroma. Together, this study shows how ARF deficiency associated with CDKN2A inactivation sculpts the PDAC TME in a p53-independent fashion. Given the central role of the TME in PDAC progression and therapeutic resistance, these findings may provide insight critical for improving therapeutic interventions for PDAC. Significance: ARF deficiency induced by CDKN2AARF alterations promotes remodeling of the pancreatic cancer microenvironment, which could provide a genotype-specific therapeutic vulnerability to improve outcomes of pancreatic cancer patients.