Gustavo Baldassarre | PubMed Health

PubMed2026

Inavolisib for PIK3CA-mutated advanced endometrial cancer: a multicentric, phase II, MITO END-4 trial.

BACKGROUND: The phosphatase and tensin homolog-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway is frequently altered in gynecological tumors, notably in endometrial cancer where PIK3CA mutations are found in nearly half of patients. Despite this, evidence of clinical activity of PI3K inhibitors in endometrial cancer is poor and limited. Alpelisib, an oral PI3K alpha-selective inhibitor, showed encouraging preliminary activity in advanced gynecological tumors harboring PIK3CA alterations. Inavolisib is a highly potent and selective PI3K inhibitor. PRIMARY OBJECTIVE(S): The MITO END-4 trial aims to assess the efficacy and safety of inavolisib in patients with endometrial cancer who have received platinum-based chemotherapy and immunotherapy. The primary objective is to determine the anti-tumor activity (assessed by objective response rate) of inavolisib in patients with advanced endometrial cancer with PIK3CA mutated tumors. STUDY HYPOTHESIS: The study tests the hypothesis that inavolisib has superior anti-tumor activity compared to historically available standard therapies in previously treated patients with advanced endometrial cancer harboring a PIK3CA mutation. TRIAL DESIGN: This is a phase II, single-arm, multicenter trial in which advanced endometrial cancer patients whose tumors harbor a pathogenic PIK3CA mutation will receive inavolisib. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients aged 18 years and older with documented evidence of PIK3CA mutated advanced endometrial cancer (endometrioid, serous, clear cell, carcinosarcoma or mixed histology) will be enrolled. Patients have previously received at least 1 platinum-based chemotherapy in any setting (adjuvant or advanced) with or without immune checkpoint inhibitor, alone or in combination. Not more than 4 lines of therapy are allowed. Key exclusion criteria include uterine sarcoma and prior treatment with any PI3K, AKT, or mechanistic target of rapamycin (mTOR) inhibitor. PRIMARY ENDPOINT(S): Objective response rate defined as a complete response or partial response by the Investigator using RECIST v1.1 criteria over the whole treatment period. SAMPLE SIZE: 48 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL: May 2028. TRIAL REGISTRATION: MITO END-4; EU-CT NUMBER: 2025-522981-61-00; NCT07522697.

Endometrial cancer↗

PubMed2025

Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.

Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions. Here, we describe the functions of CDKs, categorized into the three main functional groups in which they are classified, highlighting the most relevant pathways that drive their expression and functions. We then discuss the potential roles and deregulation of CDKs in human pathologies, with a particular focus on cancer, the human disease in which CDKs have been most extensively studied and explored as therapeutic targets. Finally, we discuss how CDKs inhibitors have become standard therapies in selected human cancers and propose novel ways of investigation to export their targeting from cancer to other relevant chronic diseases. We hope that the effort we made in collecting all available information on both the prominent and lesser-known CDK family members will help in identify and develop novel areas of research to improve the lives of patients affected by debilitating chronic diseases.

Humans↗