Tailored Therapies Research Program for Breast Cancer

In 2004, the Susan Smith Center Executive Council launched an ambitious fundraising effort to support the Tailored Therapies Research Program, with an overarching goal of promoting projects that seek to improve the treatment of women with breast cancer. This initiative was dedicated to funding investigations of potential genetic and molecular targets and to provide evidence that inhibition of these targets will be therapeutic. The Executive Council successfully completed a $3 million fundraising goal for the program in January 2007.

Funds raised by the Executive Council made a significant impact within the Tailored Therapies Research Program, helping Dana-Farber to:

• Fund early stage investigations of tailored therapies and foster scientific Collaboration
• Support six innovative research projects, each of which addresses a potential new target for treatment in breast cancer patients
• Support four key areas of research infrastructure needed to develop tailored therapies and other projects in women's cancers

Progress Notes

Project 1: NF-kB: The Master Switch in the Tumor and Surrounding Stroma
Part 1: The Stroma

Principal Investigators: Christina Scheel, MD, Robert Weinberg, PhD
Project Summary: Dr. Weinberg's laboratory pioneered our understanding of how normal "host" cells that constitute the stroma in a tumor contribute to the unwanted breast cancer "guest" cells that are growing in that stroma. Dr. Scheel believes the master regulator of cell fate, known as nuclear factor kappa B (NF-kB), regulates the signals that come from the host stroma and affects the cancer cells. She has completed novel mixing experiments, which have allowed her to study these messages and decipher the way in which the host stroma increases the malignancy of the cancer.

Project 1: NF-kB: The Master Switch in the Tumor and Surrounding Stroma
Part 2: The Tumor

Principal Investigators: Debajit Biswas, PhD, J. Dirk Iglehart, MD
Project Summary: Drs. Biswas and Iglehart found that NF-kB is activated in certain subclasses of breast cancer, particularly in the estrogen receptor negative types. In these cancers, NF-kB may play a critical role in sustaining cancer growth and survival. In fact, when these researchers disabled NF-kB, the growth of breast tumors in the laboratory was halted. They posit that the spontaneous activation of NF-kB is a potent mechanism that cancers use to escape treatment, and it may explain resistance to many treatments. Work is proceeding that examines resistance to the HER2-directed drugs, like Herceptin, and hormone treatments, like Tamoxifen or aromatase inhibitors.

Project 2: Therapeutic Targeting IGF-1 Signaling in Breast Cancer

Principal Investigators: Yoko Irie, MD, PhD, Joan Brugge, PhD, Charles Stiles, PhD
Project Summary: Drs. Brugge and Stiles are senior cancer researchers at Harvard. They used their grant to promote the important research of Dr. Yoko Irie, a Fellow in Medical Oncology and an important new faculty member at Dana-Farber and Harvard. Dr. Irie wants to exploit the role Insulin-Like Growth Factor (IGF) and its receptor (IGFR) play in breast cancer growth. Dr. Irie has established a novel culture system, a particular way of growing breast cancer cells, which can be used to measure the effect of inhibiting the IGF-IGFR signaling axis on the growth and behavior of the cancer cell. IGF inhibitors are in clinical trials, and Dr. Irie provides strong leadership in this emerging treatment strategy.

Project 3: Targeting PI3Kinase, a Dominant Oncogene in Breast Cancer

Principal Investigators: Jean Zhao, PhD, Thomas Roberts, PhD
Project Summary: Remarkable progress has been made by the Zhao and Roberts team. PI3Kinase is a signaling intermediate, a relay along the way from growth factor signals at the surface of the cancer cell to cancer cell division, controlled in the nucleus. Furthermore, PI3kinase along with p53, discussed earlier, are the most commonly mutated genes in breast cancer. Dr. Zhao has developed exquisite animal models of both PI3Kinase activation and inactivity. She can test the direct effect of targeting the several forms of PI3Kinase on the growth of cancers. Finally, she has engineered breast cells with mutated forms of PI3Kinase that grow rapidly in animals, and are used to test new PI3Kinase inhibitors entering clinical trials.

Project 4: Target Discovery: Genes on Chromosome 8q22

Principal Investigators: Zhigang Charles Wang, MD, PhD, Andrea L. Richardson, MD, PhD
Project Summary: Drs. Richardson and Wang began by searching the breast cancer genome for recurrent chromosome alterations. They found a region on chromosome 8, at a milestone called 8q22, which was amplified or present at far too many copies (the normal copy number in the human genome is two). Regions of amplification often harbor cancer-causing genes. They found that patients with amplification at 8q22 suffer treatment failure more often than women without the amplification, and generally have worse tumors. Furthermore, women with amplification at 8q22 more often suffer relapse after Adriamycin chemotherapy. This suggested that the increase of a gene, or genes, is responsible for Adriamycin sensitivity or resistance. Indeed, they have found such a gene and are beginning to understand why this gene jeopardizes treatment with Adriamycin.

Project 5: Relationship of Hereditary and Sporadic Basal-like Breast Cancer: Therapeutic Implications

Principal Investigators: Daniel Silver, MD, PhD, David M. Livingston, MD
Project Summary: BRCA1 is the first breast cancer gene identified in families with hereditary breast and ovarian cancer. Women who carry mutations in BRCA1 get "basal-like" breast cancer. Basal-like breast cancer is so-named because the cells in the cancer resemble basal cells in normal breast ducts. These tumors are always estrogen receptor negative, progesterone receptor negative and HER2-negative (they are also referred to as 'triple-negative'). Dr. Silver found that the triple-negative, basal-like breast cancer cells respond to agents that damage DNA in a manner very similar to cells that lack BRCA1 function. This suggested to Drs. Livingston and Silver that basal-like cancers might be unusually sensitive to genotoxic chemotherapy (chemotherapy that damages DNA). As a result of their careful laboratory work, a clinical trial was started at Dana-Farber for women with basal-like breast cancer by Drs. Judy Garber and Eric Winer. Cisplatinum was chosen for this unique clinical trial because it efficiently damages and destroys the cancer cells' DNA. This trial finished with extremely exciting results, and has prompted new local trials, and even national and international trials for women with basal-like cancer.

Project 6: Reversing Cisplatin Resistance in Breast and Ovarian Cancer

Principal Investigators: Jean-Bernard Lazaro, PhD, J. Dirk Iglehart, MD
Project Summary: During the course of the Tailored Therapies grant cycle, Dr. Jean-Bernard Lazaro was recruited into the WCP and began to work on the important problem of cisplatinum chemotherapy resistance in breast and ovarian cancer. The approach was to purify complexes of proteins involved in the repair of DNA damage, damage caused by cisplatinum and responsible for its anti-cancer effects. Dr. Lazaro's work led to the identification of proteins in these complexes that influence the sensitivity of cells to cisplatinum killing. Selective inhibition of some of these proteins produced both enhanced and diminished sensitivity, pointing the way to development of new targets for therapy and biomarkers for predicting chemotherapy responses.

Research Infrastructure

Core 1: Tissue and Translation

Led by Drs. Eric Winer and Andrea Richardson, strengthening the infrastructure to streamline the acquisition, storage and distribution of blood samples and cancer tissues from patients is the mission of this Core. Over 2,000 tissue samples from women with breast cancer, and more than 5,000 blood samples are now in our repository. This activity involves recruitment of patients, acquisition of informed consent, collection, storage, and final distribution to researchers at Dana-Farber and Brigham and Women's Hospital.

Core 2: Re-sequencing and Genomics

Development of rapid, high-throughput, and inexpensive gene sequencing alternatives is the goal of this Core. Led by Dr. Alexander Miron, the WCP has access to rapid gene sequencing and mutation detection, at a fraction of the cost for commercial sequencing. This enterprise is scheduled to move to the new waterfront location in space that will become Dana-Farber's "technology incubator".

Core 3: Biostatistics and Bioinformatics

Design and interpretation of genomic experiments that involve huge amounts of data and intensive computation requires a full-time biostatistician, who also has a facility with computer analysis and display programs. Dr. Lihua Zou has been supported by Executive Council funds and provides support to many Dana-Farber researchers.

Core 4: Animal Models and Pre-clinical Testing

Development of a state-of-the-art small animal testing facility and the construction of small animal models of breast cancer was the goal of this Core. Dr. Jean Zhao has provided models of breast cancer, with "forward engineered" activated genes, and tested their growth in animals. In the future, Dr. Zhao intends to engineer normal breast cells with virtually every activated kinase enzyme to create a panel of cells that will be used for drug screening and development.