Therapeutic Strategies to Stabilize and Activate PTEN in Cancers and Rare Disorders with Monoallelic PTEN Loss

PTEN (Phosphatase and Tensin Homolog) is a key tumor suppressor that regulates cell growth, survival, and proliferation by inhibiting the PI3K/AKT/mTOR signaling pathway. Monoallelic PTEN loss or inactivation—a frequent event in prostate, breast, colorectal, and lung cancers, as well as in genetic disorders such as PTEN Hamartoma Tumor Syndrome (PHTS)—creates a major therapeutic vulnerability. This proposal aims to develop novel strategies to restore PTEN function, providing innovative solutions for both cancer and PTEN-related genetic disorders.

To achieve this goal, we will implement two complementary strategies:

AIM 1: Inhibition of WWP2. WWP2 is an E3 ubiquitin ligase that drives proteasomal degradation of PTEN. Our first approach develops inhibitors that specifically block WWP2, preventing PTEN degradation and restoring its tumor-suppressor function. Through high-throughput DNA-encoded library (DEL) screening, Dr. Cavalli’s laboratory has already identified two promising inhibitors, which will now be optimized for potency, selectivity, and therapeutic potential.

AIM 2: Development of DUBTACs. The second approach engineers Deubiquitinase Targeting Chimeras (DUBTACs) to selectively recruit deubiquitinases to PTEN, removing ubiquitin chains and protecting it from degradation. This targeted strategy offers a precise method for restoring PTEN activity while minimizing off-target effects.

AIM 3: In vivo validation. Finally, we will evaluate the efficacy, bioavailability, and safety of both WWP2 inhibitors and PTEN-directed DUBTACs in preclinical models. These in vivo studies will be crucial to demonstrate therapeutic potential and prepare for clinical translation.

By combining these complementary approaches—WWP2 inhibition and DUBTAC-mediated stabilization—we aim to develop robust therapeutic tools to restore PTEN activity in contexts of partial loss.

Our team unites complementary expertise: Dr. Andrea Cavalli (computational structural biology and drug design), Dr. Andrea Mattarei (medicinal chemistry and synthesis of bioactive compounds), and Dr. Andrea Alimonti (oncology and PTEN biology). Together, this multidisciplinary team will leverage cutting-edge methods in structural biology, chemistry, and preclinical testing to drive the development of innovative therapies. With a proven track record of collaboration and impactful research, the consortium is well positioned to advance transformative solutions for PTEN-related conditions.

Importantly, this project will lay the foundation for clinical translation. With follow-up funding, we aim to move the most promising candidates into human trials, bridging laboratory discoveries with patient care and working toward meaningful improvements for individuals affected by PTEN dysfunction.