While substantial progress has been recorded in the fight against breast cancer, the burden of death and suffering inflicted upon society by this disease remain unacceptably high. In 2010, an estimated 207,090 new cases of invasive breast cancer are expected in women in the United States. About 39,840 women in the United States are expected to die from breast cancer this year. In nearly all of the cases, breast cancer deaths occur because of the invasion of distant sites in vital organs, through the process of metastasis. The genetic instability that typifies cancer becomes extreme in the late stages of the disease, and therefore, metastatic disease is usually very heterogeneous, developing many different cancer subtypes in the same patient. Each of these subtypes has different vulnerabilities to an array of drugs, making the use of combination therapies a necessity. However, to render the situation even more complex, cancer generally develops "resistance" to drugs -- a commonly accepted misnomer for the fact that even though a drug may be effective against one cancer cell type in a cancer, there are many other types present in metastatic disease, which are unaffected by the drug and thus emerge as the leading cell population that further drives the unstoppable growth of the disease. It is now broadly accepted by the cancer research community that tumor-initiating cells play a major role in drug resistance and tumor metastasis. Each cancer drug is typically effective in less than 40% of the patients who receive them (a sad statistic that unfortunately does not spare molecularly targeted therapies such as Herceptin), pointing to the fact that we do not have a sufficiently advanced cadre of biomarkers that can be used to predict efficacy of a given drug for a given patient or to monitor the efficacy of a drug efficiently. The latter is a problem of immense tragic consequence, since each attempt to find by-trial-and-error the "right" drug combination of drugs takes a great toll of suffering on the patient and limits the ability to undergo additional attempts at personalized therapeutic combinations.

In our 2008 Innovator Award, we proposed novel approaches that address the currently unmet necessity of personalization in breast cancer medicine by developing technology platforms for multistage delivery of therapeutic agents, nanochips for proteomic analysis, and implantable "nanoglands" for the controlled release of anti-cancer drugs. In the course of our investigations, we have now identified new challenges and opportunities for transformational progress in breast oncology. This proposal is aimed at capitalizing on these opportunities through an approach that leverages the discoveries in our 2008 Innovator Award, but has no overlap with it, and actually was unimaginable at the time of the 2008 Innovator Award submission.

We will prioritize three focus areas: (1) Identification of essential genes and pathways that contribute to therapy resistance to yield the best-suited combination of therapeutic agents for a patient, and specific lesions. We will focus on personalized combinations of established drugs, as well as in synergy with novel classes of agents such as siRNAs to target therapy-resistant cells. Once this combination is identified, the cocktail therapy can be delivered in conventional manners, through novel embodiments of our multistage vectors (MSV). This part of the project will be developed jointly with a world-renown expert who was not part of the original 2008 Innovator team: Dr. Jenny Chang, breast medical oncologist and Director of our Cancer Center of Excellence. The program will be under the management of breast cancer expert and pharmaceutical development specialist Dr. Haifa Shen. (2) Development of novel methods for the delivery of MSV to target lesions. We have very recently observed that there are classes of cells that spontaneously "home" to tumors. In collaborations with Dr. Ennio Tasciotti, we plan to capitalize on this observation to use the patients' own cells as personalized "Trojan horses" to bring the MSV and their personalized combinations of drugs to primary and metastatic lesions. (3) Correlation of genomic and proteomic signatures with therapy resistance mechanisms. Better understanding of resistance mechanism will result in development of new therapy strategies in the fight against human cancers.

Success in even a small fraction of the proposed plan will yield transformational advances against metastatic breast cancers.