Titles and Affiliations
Professor of Medicine
Chief, Breast Medical Oncology
Co-Director, Yale Cancer Center Genetics and Genomics Program
Research area
Identifying novel therapeutic targets in patients with aggressive breast cancer.
Impact
While major advances have been made in breast cancer treatment, many patients still face limited options when their cancer stops responding to standard therapies. Antibody-drug conjugates (ADCs), which deliver chemotherapy directly to cancer cells, have shown great promise, but current approved ADCs only target a small number of molecular cancer markers, and not all patients benefit. At the same time, breast cancers are highly diverse, even within a single tumor, and cancer cells can behave differently and respond unevenly to treatment. These challenges highlight the urgent need to discover new drug targets and develop a better understanding of the complex makeup of breast tumors, providing more options to patients and hope for long term benefit.
Progress Thus Far
Dr. Pusztai and his team identified a protein called Nectin-2, which is present in about 70 percent of breast cancers, and developed a novel ADC that binds Nectin-2 specifically. In parallel, the team studied breast cancers with intermediate levels of estrogen receptor (ER) expression, using advanced tissue-mapping technology to determine whether these tumors are made up of a mix of different cancer cell types, or a single cancer type with some cells that have simply lost their ER expression. They found that the ER-negative regions within these tumors closely resembled a more aggressive cancer subtype. They observed a pattern suggesting these regions may resist hormone therapy but remain more sensitive to chemotherapy. Separately, the team made progress identifying two new potential drug targets based on genomic analysis of breast cancers and has begun generating early laboratory data to support their development into future therapies.
What’s next
Dr. Pusztai and his team are now testing their novel Nectin-2 targeting ADC in experiments that closely model human breast cancer. They will also begin a new project to design a drug that targets a metabolic vulnerability in cancer cells, using a drug-design approach that tags and degrades the target protein. If successful, this work could add new targeted therapy options for patients with aggressive, treatment-resistant breast cancer.
Biography
Lajos Pusztai, MD, DPhil is Professor of Medicine at Yale University and Chief of the Breast Medical Oncology Section at the Yale Cancer Center. He is also Co-Director of the Cancer Center Genomics and Genetics Program. Dr. Pusztai received his medical degree from the Semmelweis University of Medicine in Budapest, and his DPhil. degree from the University of Oxford in England.
His research group has made important contributions to establish that estrogen receptor-positive and-negative breast cancers have fundamentally different molecular, clinical and epidemiological risk characteristics. He has been a pioneer in evaluating gene expression profiling as a diagnostic technology to predict chemotherapy and endocrine therapy sensitivity and have shown that different biological processes are involved in determining the prognosis and treatment response in different breast cancer subtypes. His group has also developed new bioinformatics tools to integrate information from across different data platforms in order to define the molecular pathways that are significantly disturbed in individual cancers and could provide the bases for future individualized treatment strategies. He made important contributions to clarify the clinical value of neoadjuvant chemotherapy in different breast cancer subtypes.
Dr. Pusztai is also principal investigator of several clinical trials investigating new drugs and potential response markers. He has published over 200 manuscripts in high impact medical journals and is the Clinical Editor of the British Journal of Cancer, Member of the Scientific Advisory Board of the Breast Cancer Research Foundation, Member of the Breast Cancer Steering Committee of the NCI and Co-Chair of the Trans-ALTTO Committee that oversees the translational research projects of tissues collected during two larger randomized clinical trials (ALTTO and NeoALTTO). He is also Chair of the Data Safety Monitoring Committee of the OPTIMA trial.
