Dana–Farber Cancer Institute is a comprehensive cancer treatment and research institution in Boston, Massachusetts. Dana-Farber is the founding member of Dana–Farber/Harvard Cancer Center, Harvard's Comprehensive Cancer Center designated by the National Cancer Institute, and one of the 15 clinical affiliates and research institutes of Harvard Medical School. Currently, Dana-Farber is ranked the #3 cancer hospital in the world. Two Nobel laureates in Physiology or Medicine are among its past and present faculty. Dana-Farber's research discoveries include the development of the highly successful Gleevec to treat chronic myeloid leukemia.
Purpose Chemotherapy-induced peripheral neuropathy (CIPN) is associated with a large amount of interindividual variability in signs and symptoms. The purposes were to use latent profile analysis to identify subgroups of survivors with distinct lower extremity (LE) loss-of-function CIPN profiles; evaluate for differences in demographic, clinical, and pain characteristics between the profiles and characteristics associated with membership in the more severe profile; and examine relationships between the profiles and measures of large fiber loss and C-tactile fiber function. Methods LE loss-of-function CIPN profiles were created using measures of worst pain, loss of light touch sensation, loss of cold sensation, loss of pain sensation, vibration threshold, and two balance measures. Results Of the 405 survivors evaluated, two distinct profiles were identified: less severe loss of LE function (76.5%) and more severe loss of LE function (23.5%). Risk factors for membership in the more severe profile included being older, male, and having lower functional status. In terms of the loss of large fiber function, survivors in the more severe class had four more sites on average that lost light touch sensation; their vibration thresholds were 1.5 times higher; and their ratings of numbness were significantly higher. For C-tactile fiber function, significant between-group differences were found in survivors' ratings of the severity of sensitive skin and unpleasantness. Conclusions Findings suggest that distinct "CIPN phenotypes" can be identified in cancer survivors. Detailed phenotyping and molecular characterization of various CIPN phenotypes will lead to the development and testing of targeted and personalized interventions.
Loss of the tumor-suppressor PTEN drives cancer progression and therapeutic resistance, yet no targeted therapies exist for PTEN-deficient tumors. In this study, we identify a critical druggable mechanism in which PTEN loss induces PI3Kβ phosphorylation for tumorigenesis. Using the BioID interactome, we uncovered a phosphorylation-dependent PI3Kβ-EPHA2 interaction in PTEN-null cells, driven by p-PI3KβY962. PTEN functions as a tyrosine phosphatase that normally dephosphorylates p-PI3KβY962. In PTEN-deficient contexts, enhanced p-PI3KβY962 forms a complex with EPHA2 and SRC, in which both kinases contribute to PI3Kβ phosphorylation, activating oncogenic pERK/c-MYC and pAKT pathways. We developed a selective p-PI3KβY962 antibody detecting p-PI3KβY962 in PTEN-deficient tumors across preclinical models and clinical tumor specimens. Disrupting p-PI3KβY962 suppressed tumor growth in multiple PTEN-null models. Dasatinib, an FDA-approved SRC/EPHA2 inhibitor, effectively reduced p-PI3KβY962 and inhibited tumor progression in PTEN-null but not PTEN wild-type tumors. These findings establish p-PI3KβY962 as a druggable target and biomarker for developing targeted therapy in PTEN-deficient cancers beyond conventional PI3K kinase inhibition. SIGNIFICANCE:We revealed a critical new mechanism that PTEN loss induces PI3Kβ phosphorylation and EPHA2/SRC/p-PI3KβY962 complex signaling to drive tumorigenesis. This work directs pharmaceutical development of p-PI3KβY962 inhibitors and biomarker-driven clinical trials repurposing dasatinib for PTEN-deficient solid tumor treatment, with potential to significantly improve outcomes of broad patients with PTEN-deficient tumors.
PURPOSE:The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. METHODS:We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS:PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION:PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator-naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. While primary HLH presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, secondary HLH more commonly presents in adults and is a heterogenous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. Yet, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis and management of this life-threatening condition. Note that primary HLH is reviewed separately as a companion article in this review series.
