Maurizio Scaltriti is an Associate Professor at Memorial Sloan Kettering Cancer Center and runs a laboratory that works back to back with physicians of the Early Drug Development Service. The main focus of his team is the identification of novel mechanisms of resistance to targeted therapy and to provide insights to better select patients who are more likely to benefit from specific treatments.
During the past 15 years, Dr Scaltriti focused his research upon understanding how the selective pressure imposed by targeted therapy modifies the evolution of drug resistance in breast cancer. He discovered that truncated forms of HER2, lacking the extracellular domain, limit the activity of the FDA approved anti-HER2 antibody trastuzumab. Moreover, he found that amplification and/or overexpression of cyclin E negatively correlates with clinical response to trastuzumab-based therapy. Concurrently, he proposed new therapeutic strategies to overcome or delay the emergence of such resistance. One example is dual HER2 blockade using trastuzumab and lapatinib in combination, showing superior results compared to single agent therapy both in preclinical models and in the clinical setting. Moreover, he discovered that, among the HER2-positive tumours, there is a subset that is more dependent on HER2 for survival and is exquisitely sensitive to anti-HER2 therapy.
In the field of PI3K inhibitors, Dr. Scaltriti proposed that PI3K blockade can be combined with PARP inhibition in triple negative breast cancer models or with mTORC1 inhibitors or anti-endocrine therapy in PIK3CA-mutant models to achieve synergistic antitumour activity. Moreover, he contributed to the discovery that sustained mTOR activity can limit the efficacy of PI3Kα-specific inhibitors in both head and neck and breast cancers, and that mTORC1 activity can be sustained also in a PI3K-independent manner via activation of either the EGFR-PKC axis or the PDK1-SGK1 signalling. He also demonstrated that progressive loss of PTEN expression leads to acquired resistance to PI3Kα-specific inhibition in breast cancer. More recently, he co-led a seven-year long project that resulted in the discovery that approximately 15% of PIK3CA mutant breast cancers carry two distinct PIK3CA mutations in the same. Importantly, Dr. Scaltriti uncovered that dual PIK3CA mutant tumours have hyperactive PI3K pathway and are exquisitely sensitive to the antitumour activity of specific PI3K inhibitors.
In 2016, Dr. Scaltriti was appointed Associate Director of Translational Science of the Center for Molecular-Based Therapy and he broadened his research interests in the characterisation of actionable genomic alterations found in solid tumours and in studying novel drug delivery platforms. Examples of these studies are the discovery that convergent mechanisms activating the MAPK pathway in NTRK-fused solid tumours can result in resistance to 1st- and 2nd- generation TRK inhibitors and that HER2 altered lung tumours respond to antibody-drug conjugates in combination with irreversible HER2 inhibitors.
Dr Scaltriti is internationally recognised as an opinion leader in targeted therapy and translational science, bridging the gap between the clinic and the laboratory. One of his mission is also to bring cutting edge treatments to the real world, working tirelessly to render novel efficacious treatments accessible to every patient.