Fellow, Surgical Oncology
University of Toronto/Sunnybrook Research Institute
Although recent advances in treatments have helped improve the survival of breast cancer patients, the development of new therapies has been a challenging process. Only a small number of therapeutic agents tested in the laboratory have demonstrated efficacy in clinical trials. It would be ideal if laboratory (in‐vitro) models could better predict therapeutic efficacy in patients. Cancer cell lines, or immortalized cancer cells derived from patients, have commonly been used to model cancer subtypes and test therapeutic efficacy. However, the growth of cancer cells and their response to therapy has been shown to be influenced by proteins in their surrounding microenvironment. Therefore, Dr. Hassan proposes to determine the efficacy of a therapeutic agent in a recently developed model called a microenvironment microarray, a high‐throughput technology that can assess the influence of a panel of microenvironment proteins upon different cellular functions. This project will focus on a PARP inhibitor, a targeted therapeutic agent known to affect DNA damage and repair mechanisms. This agent has previously been demonstrated mixed results in clinical trials, and so there is still a need to identify which breast cancer patients will benefit from this agent. Currently, this inhibitor is also being tested in a clinical trial called the I SPY2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis) for breast cancer patients with locally advanced disease receiving treatment prior to surgery. This trial aims to improve treatment regimens for patient subsets on the basis of molecular characteristics. Therefore, Dr. Hassan’s overarching hypothesis is that prediction of therapeutic response to the PARP inhibitor in breast cancer patients can be modeled in the laboratory using the microenvironment microarray.
Dr. Hassan’s project tightly links the preclinical and clinical evaluation of PARP inhibition using a microenvironment model and patients from a clinical trial. Although the genomic predictors identified will need to be validated, this laboratory model shows great potential to select patient populations prior to administration of novel therapies in the future.
The overarching goal of this project is to identify specific alterations in the tumor genome that are predictive of response to PARP inhibition in breast cancer patients. The first component takes place in the laboratory and involves identifying genomic changes in breast cancer cell lines, or immortalized cancer cells, which are predictive of response to PARP inhibition. Dr. Hassan has used a real-time, automated, imaging-based output, whereby cells are grown in a 96-well plate and imaged by a microscope every 3 hours, and the therapeutic effect upon cell growth inhibition or cell death can be determined. To date, she has found good performance of the assay using the robot, wherein the controls were working well and the PARP inhibitor alone has demonstrated a good response. Ongoing work consists of testing more cell lines and to identify an improved response using the PARP inhibitor in combination with other agents. She will also be using a microscope that detects fluorescence in order to analyze more specific effects of PARP inhibition upon DNA. Subsequently, she plans to use the microenvironment microarray to determine the impact of microenvironment proteins upon cellular response to PARP inhibition in a high-throughput manner, and to identify genomic predictors of response using sophisticated computer programs. The second component of the project consists of comparing the predictors of response discovered in the laboratory to those identified from breast cancer patients who were treated with the same PARP inhibitor in the I SPY 2 TRIAL. Preliminary results of this clinical trial were recently presented at the San Antonio Breast Cancer Symposium in December 2013. 72 patients were randomized to receive the PARP inhibitor/carboplatin combination and demonstrated an improved rate of tumor shrinkage compared to controls. Therefore, with clinical evidence demonstrating efficacy of the PARP inhibitor, Dr. Hassan and her colleagues are striving to identify, by genomic analysis in the laboratory, a breast cancer subtype which will most benefit from PARP inhibition.
Born and raised in Montreal, Dr. Saima Hassan completed medical school and residency in general surgery at McGill University. During residency, she spent four years outside of clinical training to complete a doctorate in translational breast cancer research, also at McGill University. She discovered the first host‐derived blood marker predictive of distant metastasis in breast cancer: stromal cell‐derived factor (SDF)‐1. She also studied the dysfunctional relationship between the tumor and the host and its role as a prognostic marker. Furthermore, she performed chemosensitivity studies in transgenic mice, testing the efficacy of a CXCR4 antagonist in inhibiting primary tumor growth and distant metastasis.
Dr. Hassan won several awards during her doctoral studies including a Breast Cancer Achievement Award from the Lynn Sage Breast Cancer Symposium, the Canadian Research Award for Specialty Residents from the Royal College of Physicians and Surgeons of Canada, and awards from the Canadian Institutes of Health Research. She then went to pursue a clinical fellowship in surgical oncology at the University of Toronto. Dr. Hassan will now embark on further research training under the supervision of Dr. Joe Gray at Oregon Health Sciences University to study the role of a recently developed technology that will incorporate the interactions between breast cancer cells and proteins in their microenvironment in order to identify genomic predictors of therapeutic response in the laboratory.