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Research Grants Awarded
Human and Mouse Linked Evaluation of Tumors (HAMLET)
Tumor Cell Biology VI
Breast Cancer is a complex disorder comprised of a spectrum of cancer subtypes with distinct clinical phenotypes, genetic anomalies and therapeutic responsiveness. This proposal is part of an ambitious and highly collaborative plan to identify the anomalous gene functions that orchestrate a breast cancer patient?s fate. Documenting all the somatic mutations underlying cancer development is the goal of the Cancer Genome Atlas (TCGA) project sponsored by the NCI. It is not an exaggeration to state that the final version of the Breast Cancer Genome Atlas (BCGA) will include thousands of tumor-specific DNA anomalies. The challenge ahead is to determine which of these DNA changes are pivotal in driving the cancer phenotype, which ones are useful biomarkers and which ones represent genuine therapeutic opportunities. This grant focuses on the development of new research techniques for functional annotation of the BCGA to narrow the knowledge gap between breast cancer genome structure and function. Hypothesis: Primary Breast Cancers engrafted into the Human in Mouse model maintain the genetic structure and gene expression pattern of the original tumor. New techniques in mouse xenografting termed ?Human in Mouse? have overcome low success rates traditionally associated with attempts to grow human tumors in immunocompromised mice. To begin to rigorously evaluate this technique we proposed the following four specific aims (SA): SA 1: Conduct the HAMLET (Human And Mouse Linked Evaluation of Tumors) clinical trial to generate 40 new tumor lines in NOD SCID mice from patients undergoing systemic therapy. SA 2: To compare global gene expression analysis between the tumor and its counterpart xenograft. SA 3: To compare mutational profiles in TP53, PTEN and PIK3CA between the tumor and its counterpart xenograft. SA 4: To compare the pattern of DNA gains and losses between the tumor and its counterpart xenograft by array comparative genomic hybridization. If we are successful in this project one can envisage a remarkable acceleration in both biomarker and therapeutic research because we will be much more confident that preclinical findings are relevant to the clinical situation. Examples of the potential utility of the HAMLET research approach includes: 1) The ability to systematically work through the list of BCGA abnormalities using techniques such as gene transfer (to correct losses) and RNA interference (for amplified genes) to assign function; 2) DNA and/or mRNA profiles associated with resistance or sensitivity to individual therapies could be documented and validated; 3) New agents could be tested more rigorously in mouse models before proceeding to human studies as there would be more confidence that mouse experiments are predictive of clinical outcomes.
Breast Cancer is a complex disease with patients experiencing very different fates. Some are cured with surgery alone and others suffer repeated relapses of their disease despite all available treatments. One of the major reasons for these very different outcomes is that at the DNA level, breast cancers are remarkably diverse. In fact the constellations gene changes may be unique to every cancer. However, if we could fully document all these DNA changes we believe we would begin to understand how patients can experience such different outcomes. Documenting the DNA changes in cancer is the goal of the NCI funded Cancer Genome Atlas (TCGA). It is likely that the final version of the "Breast Cancer Genome Atlas" (BCGA) will include thousands of tumor-specific DNA anomalies. The challenge ahead is to determine which of these DNA changes are important so we can use the information to predict outcomes and design new drugs. Hypothesis: Primary Breast Cancers engrafted into mice are faithful copies of the original tumor. New techniques in mouse xenografting termed "Human in Mouse (HIM)" have overcome the barrier of low success rates traditionally associated with attempts to grow human tumors in mice. To evaluate this new technique we will obtain breast cancer tissue from patients about to undergo chemotherapy before surgery to shrink their breast cancer. We term these studies "HAMLET" for "Human and Mouse Linked Evaluation of Tumors" because we can follow the clinical outcomes and a copy of the tumor in a mouse to see if the mouse copy behaves the same way as the original cancer in the clinical setting. In our proposal we will conduct careful and detailed experiments to determine if the mouse tumor is a true copy of the original cancer. If we are successful one can envisage a remarkable acceleration in breast cancer research because we will be much more confident that preclinical mouse findings are relevant to the clinical situation. Examples of the potential utility of the HAMLET research approach include: 1) The ability to systematically work through the DNA changes to work out which ones are critical to tumor formation; 2) New insights as to why tumors are sensitive or resistant to treatment; 3) New agents could be tested more rigorously before proceeding to human studies because there would be more confidence that mouse experiments are predictive of clinical outcomes.