Lajos Pusztai, MD, D.Phil

2009-2010 BCRF Project:
New laboratory methods developed in the past few years made it possible to examine all genes that are expressed in a small piece of human breast cancer and also to assess whether the genes are normal or defective. Anti-estrogens such as tamoxifen and the anti-HER2 antibody trastuzumab represent the only two currently available highly effective therapies for breast cancer that are targeted at particular molecular subsets of this disease, estrogen receptor-positive and HER-2-positive cancers respectively.

Dr. Pusztai's goal is to discover the next generation of drugs that are targeted to specific genomic abnormalities in human breast cancer. He and his team have performed detailed gene copy number analysis of 103 early stage breast cancers and identified frequently amplified or deleted genes. On average, 76 different chromosomal abnormalities were detected in single tumors. This indicates that every breast cancer harbors a large number of molecular abnormalities and there is great individual variability between cancers. Next they will test in the laboratory that some of the genes that show increased copy numbers may play an important biological role in the survival of these cancers. Among the most frequently altered (i.e. amplified) genes is fibroblast growth factor receptor 1 (FGFR1). In the current, second phase of this project the researchers will investigate the biological role of FGFR1 in breast cancer using experimental models in the laboratory.

In a separate project, funded through an ASCO Advanced Clinical Research Award, Dr. Pusztai is leading a prospective clinical trial, to find out if any one of three different molecular response predictors can identify a group of patients with metastatic breast cancer who have an at least a 25% chance to clinically benefit from the drug dasatinib. Clinical benefit is defined as either no change or decrease in the size of the cancer during treatment. The three different predictors that will be tested in this study are each based the expression of a relatively large number of genes. Dr. Pusztai and his tema have defined the three predictors and submitted these results for publication in January 2009, so that these become available for the larger scientific community for study. They have also secured all the necessary institutional and FDA approvals to start the clinical trial that will employ these tests to select patients for dasatinib therapy, and have also obtained further funding to conduct the trial. The trial was opened in June 2009.

Mid-Year Progress Report:
The goal of Dr. Pusztai's research is goal is to discover the next generation of drugs that are targeted to specific genomic abnormalities in human breast cancer. To date, he and his team have identified over 600 genes that have unusually high level of expression in estrogen, progesterone and HER2 receptor-negative (triple-negative) breast cancer. They artificially blocked the expression of each of these genes in 16 different breast cancer cell lines grown in the laboratory to find out which of these genes play a critical role in sustaining the growth of triple-negative breast cancers. Analysis of this data is currently underway. Genes that show strong effect in this experiment will be considered potential therapeutic targets and will be studied further with the goal of developing drugs against them.

Through an ASCO Cancer Foundation Career Development Award, Dr. Pusztai is leading an ongoing prospective therapeutic clinical trial which is among the first studies that use gene signatures to select patients for therapy with a new biologically targeted drug, dasatinib. The main objective is to find out if any of 3 different molecular response predictors can identify a group of patients with metastatic breast cancer who have an at least a 25% chance to clinically benefit from this drug. Clinical benefit is defined as either no change or decrease in the size of the cancer during treatment. The three different predictors that are tested in this study represent 3 gene expression signatures that are tested in a biopsy of the metastatic cancer. The study opened for accrual in July 2009 and since that time 25 patients have enrolled.

Bio:
Dr Pusztai leads the pharmacogenomic program in the Department of Breast Medical Oncology at MD Anderson Cancer Center. He received his MD degree from the Semmelweis University of Medicine in Budapest, and his D.Phil. from the University of Oxford in England. He is currently Professor of Medicine. He is a practicing medical oncologist and clinical researcher who published over 150 peer-reviewed articles on the biology and treatment of breast cancer.

His research focuses on the developing pharmacogenomic markers of response to therapy and identifying methods to select the optimal treatment for individual patients. His group has proposed new clinical trial designs for predictive marker evaluation, introduced new pathologic measurements of residual cancer after neoadjuvant chemotherapy, created web-based chemotherapy response prediction models based on routine clinical variables and proposed genomic markers of chemo- and endocrine-therapy sensitivity.

Dr Pusztai is principal investigator of several clinical trials investigating new drugs and potential response markers. His research is supported by grants from the National Cancer Institute, the US Department of Defense, the American Society of Clinical Oncology, The Breast Cancer Research Foundation and philanthropic research grants.