Cancer Discov
· 2026 May · PMID 41931543
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Relacorilant, a first-in-class glucocorticoid receptor antagonist, earned approval on March 25 for platinum-resistant ovarian cancer, after phase III data showed it improved progression-free and overall survival when add...Relacorilant, a first-in-class glucocorticoid receptor antagonist, earned approval on March 25 for platinum-resistant ovarian cancer, after phase III data showed it improved progression-free and overall survival when added to chemotherapy. Because its use does not depend on tumor biomarker status, the therapy could reach a broader patient population than recently approved alternatives.
Goyette MA, Graser C, Seehawer M
… +13 more, Patmanidis A, Rojas Jimenez E, Kamat A, Yan P, Fassl A, Foidart P, Li Z, James A, Sflomos G, Brisken C, Sicinski P, Michor F, Polyak K
Intratumor heterogeneity for HER2 in HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatments for HER2 heterogeneous tumors has been hindered by the lack of preclini...Intratumor heterogeneity for HER2 in HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatments for HER2 heterogeneous tumors has been hindered by the lack of preclinical models that accurately mimic the human disease. Here we describe human HER2 heterogeneous breast cancer models composed of ERBB2 amplified (HER2hi) and non-amplified (HER2lo) cell populations derived from the same tumor. Utilizing these models, together with cellular barcoding, we demonstrate subclonal cooperation between HER2hi and HER2lo subpopulations. Furthermore, HER2lo cells drive resistance to HER2-targeting antibody-drug conjugates (ADC) like T-DXd but are sensitive to HER2 kinase inhibitors. CRISPR screens in heterogeneous co-cultures identified sensitizers of HER2lo cells to T-DXd including ABCC1 and USP9X. USP9X inhibition enhances the lysosomal targeting of HER2, thereby potentiating ADC payload release and reducing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors.
Cancer Discov
· 2026 Apr · PMID 41918359
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In a recent study by Shah, Cogrossi, and colleagues, patients with overweight/obesity and pre-myeloma diseases (monoclonal gammopathy of undetermined significance or smoldering myeloma) were mailed 12 weeks of high-fiber...In a recent study by Shah, Cogrossi, and colleagues, patients with overweight/obesity and pre-myeloma diseases (monoclonal gammopathy of undetermined significance or smoldering myeloma) were mailed 12 weeks of high-fiber meals, provided with nutritional counseling, and required to track their food intake and weight. The intervention was well tolerated and improved quality of life, metabolic health, gut microbiome composition, and immune system function while supporting stable or improved multiple myeloma disease trajectories. See related article by Shah et al., p. 697.
Emerging knowledge, integrative frameworks, and multidisciplinary partnerships together create an unprecedented opportunity to advance cancer prevention through precision. By combining multimodal risk assessment with cau...Emerging knowledge, integrative frameworks, and multidisciplinary partnerships together create an unprecedented opportunity to advance cancer prevention through precision. By combining multimodal risk assessment with causal biological insight and dynamic models of early carcinogenesis, precision prevention can enable actionable, equitable, and acceptable preventive and interception strategies.
The study by Fece de la Cruz, Varkaris, and colleagues uncovered a critical mechanism underlying resistance to the p53-Y220C reactivator rezatapopt in the PYNNACLE clinical trial. Specifically, rezatapopt treatment was s...The study by Fece de la Cruz, Varkaris, and colleagues uncovered a critical mechanism underlying resistance to the p53-Y220C reactivator rezatapopt in the PYNNACLE clinical trial. Specifically, rezatapopt treatment was shown to select for secondary mutations in the TP53 gene on the Y220C-mutant background, thereby abrogating its therapeutic efficacy. See related article by Fece de la Cruz et al., p. 677.
Colorectal cancer incidence is rising globally among individuals younger than 50 years and remains poorly explained by established risk factors. In this study, we advance the hypothesis that early-childhood exposure to m...Colorectal cancer incidence is rising globally among individuals younger than 50 years and remains poorly explained by established risk factors. In this study, we advance the hypothesis that early-childhood exposure to mutagen-producing bacteria contributes to lifetime colorectal cancer risk by imprinting oncogenic mutations in the developing colorectal epithelium, thereby initiating tumorigenesis decades before clinical diagnosis and redefining early-onset colorectal cancer as a disease rooted in early-life mutagenic exposure.
Advances in technology, clinical innovation, cross-sector collaboration, and active societal engagement are converging to shift cancer from an unexpected and lethal disease to a condition that can be detected early, inte...Advances in technology, clinical innovation, cross-sector collaboration, and active societal engagement are converging to shift cancer from an unexpected and lethal disease to a condition that can be detected early, intercepted effectively, and ultimately prevented. Framed around seven core principles: purpose, prevalence, potential, precision, practicality, partnership, and persistence, this commentary highlights how strategic alignment across these dimensions can catalyze progress toward global cancer interception.
Cancer cells can repurpose a fundamental bone development program to escape therapy in a dormant state. This finding offers a way to detect cancer dormancy and assess recurrence risk using routine bone scans. See related...Cancer cells can repurpose a fundamental bone development program to escape therapy in a dormant state. This finding offers a way to detect cancer dormancy and assess recurrence risk using routine bone scans. See related article by Sreekumar et al., p. 781.
Increasing knowledge in molecular biology, enabled by multiomic technologies, data science, and global collaboration, extends cancer research beyond advanced disease settings toward earlier detection, interception, and m...Increasing knowledge in molecular biology, enabled by multiomic technologies, data science, and global collaboration, extends cancer research beyond advanced disease settings toward earlier detection, interception, and more effective therapies. Through partnership, workforce development, and a commitment to equity and trust in science, discovery can be catalyzed into meaningful patient impact.
Global clinical oncology research is experiencing a profound structural shift, evolving from a historical underrepresentation of minority groups in Western-centric trials to a new representational imbalance marked by an...Global clinical oncology research is experiencing a profound structural shift, evolving from a historical underrepresentation of minority groups in Western-centric trials to a new representational imbalance marked by an increasing reliance on Chinese patient populations due to the nation's accelerating drug research and development. This article dissects this changing dynamic and proposes a systematic framework for a next-generation global oncology research and development paradigm that is inherently more inclusive, generalizable, and efficient for all patients worldwide.
Precision oncology has transformed cancer care, but its benefits remain unevenly distributed because of persistent gaps in resources and representation. Integrating multiomics data, clinical trial evidence, and real-worl...Precision oncology has transformed cancer care, but its benefits remain unevenly distributed because of persistent gaps in resources and representation. Integrating multiomics data, clinical trial evidence, and real-world data enables the identification of both biological and extrinsic drivers of cancer inequities and can further advance treatment decisions across diverse populations worldwide.
Metastasis is a multiorgan disease in which disseminated cancer cells undergo profound, tissue-specific reprogramming that reshapes their identity, vulnerabilities, and therapeutic responses. We argue for an organ-inform...Metastasis is a multiorgan disease in which disseminated cancer cells undergo profound, tissue-specific reprogramming that reshapes their identity, vulnerabilities, and therapeutic responses. We argue for an organ-informed precision oncology framework that integrates these site-imposed programs into treatment design.
We propose a physics-based framework in which cancer cell state is defined by position and velocity in a continuous space of directly measurable physical variables-cell surface area (S) and volume (V)-and motion through...We propose a physics-based framework in which cancer cell state is defined by position and velocity in a continuous space of directly measurable physical variables-cell surface area (S) and volume (V)-and motion through S-V space as an interpretable proxy for plasticity. Therapy generates S-V vector fields that govern trajectories, enabling the design of drug combinations to steer heterogeneous cell populations toward nonviable states, offering a predictive and physically interpretable alternative to therapies directed against oncogenic mutations and/or predefined cell subpopulations.
Cancer Discov
· 2026 May · PMID 41911322
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An experimental PROTAC drug designed to degrade mutant KRASG12D produced tumor responses in patients with advanced non-small cell lung cancer and pancreatic ductal adenocarcinoma in a phase I trial, with limited toxicity...An experimental PROTAC drug designed to degrade mutant KRASG12D produced tumor responses in patients with advanced non-small cell lung cancer and pancreatic ductal adenocarcinoma in a phase I trial, with limited toxicity. Investigators are now testing the therapy in combination regimens and later-stage studies as competition intensifies among companies developing drugs against the common cancer driver.
Cancer Discov
· 2026 May · PMID 41894698
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Two studies show that cancer cells co-opt the integrated stress response, via the transcription factor ATF4, to drive both metastasis and immune evasion. Targeting this pathway or its downstream effectors, such as glutam...Two studies show that cancer cells co-opt the integrated stress response, via the transcription factor ATF4, to drive both metastasis and immune evasion. Targeting this pathway or its downstream effectors, such as glutamine metabolism and the secreted protein LCN2, may offer a way to limit tumor spread and restore antitumor immunity.