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Chk1- And Pi3K-Pathways As Therapeutic Targets In Triple Negative Breast Cancers
Investigator Initiated Research
Advanced triple negative (estrogen receptor (ER) negative, progesterone receptor (PgR) negative and HER-2/neu negative) breast cancer presents a significant clinical challenge, for which only limited treatment options exist. The high frequency of TP53 and PTEN mutations in this breast cancer subtype indicates pharmacological approaches that target defects in cell cycle checkpoints and phosphoinositol-3-kinase (PI3K) signaling may be effective. UCN-01 (7-hydroxystaurosporine), a broad-spectrum, serine-threonine protein kinase inhibitor targets the checkpoint kinase Chk1 and the PI3K signaling mediator PDK1 and therefore, may be useful in treating triple negative breast cancers. Indeed, while carrying out a phase I study of UCN-01 in combination with irinotecan in solid tumors, we observed responses in 4 out of 4 metastatic triple negative breast cancer patients. Partial responses were observed in 2 of the four patients and stable disease was observed in the other two. As a result, the Cancer Therapy Evaluation Program approved an extension of the study to determine the efficacy, tolerability and pharmacodynamic parameters of irinotecan/UCN-01 in the triple negative breast cancer population. We will test the hypothesis that the success of combining irinotecan (DNA damaging agent) with UCN-01 (protein kinase inhibitor) in triple negative breast cancers is due to the ability of UCN-01 to induce checkpoint bypass specifically in p53 deficient tumors (through Chk1 inhibition) and/or to inhibit PI3K signaling (through PDK1 inhibition). These studies will be carried out using a novel mouse model in which pre-therapy patient tumor specimens are engrafted into the ?humanized? mammary pad of NOD/SCID mice and the initial xenograft tumor is then transplanted into additional mice for experimental treatment and pathway studies that parallel the human studies. This approach, named HAMLET for Human and Mouse Linked Evaluation of Tumors, will be used to model the irinotecan/UCN-01 clinical trial, which is currently enrolling patients with triple negative breast cancer. To date, we have had an ~75% success rate in establishing the initial tumor xenograft in mice and a 100% success rate in subsequent tumor passages. Importantly, expression profiling demonstrated that the characteristics of the human tumor are preserved in the mouse xenograft suggesting that it is a valid model with which to study triple negative disease. Finally, Chk1 inhibitors that have a narrower spectrum of activity will be assessed using the HAMLET model. Similarly, inhibitors of the PI3K pathway may be investigated in these models if our initial evaluation of UCN-01 activity suggests that PI3K pathway inhibition is a critical component of this agent's therapeutic effect. The triple negative breast cancer HAMLET model will allow a preclinical evaluation of newer generations of Chk1- and PI3K-inhibitors, increasing the chances of future clinical trial success in humans.
AIM 1. Subdivide Triple Negative Breast Tumors with respect to p53 status and integrity of the PI3K pathway.
AIM 2. Develop robust pharmacodynamic biomarkers to address the mechanism of anti-tumor effect of UCN-01 and irinotecan either alone or in combination in HAMLET models.
AIM 3. Combine irinotecan with more selective Chk1 inhibitor (Go6976) in HAMLET model.
AIM 4. Perform preclinical trial in HAMLETs using optimal dosing and scheduling parameters determined in Aim 3 to assess anti-tumor effect of irinotecan and Go6976.
Breast cancer affects over 200,000 patients a year in the United States and close to a million women world-wide. Triple negative (estrogen receptor (ER) negative, progesterone receptor (PgR) negative and HER-2/neu negative) breast cancer represents ~20% of breast tumors and carries a particularly poor prognosis. Clinically, triple negative breast cancer presents a significant treatment challenge, as there are no targeted therapies available to treat this breast cancer subtype. Triple negative breast cancer is particularly prevalent in pre-menopausal women, BRCA1 carriers and in African American women. Up to 33% of breast cancer among underserved, pre-menopausal, African American women is of the triple negative subtype. The limited therapeutic options for this breast cancer subtype is a major contributory factor to the poor clinical outcome observed in African American breast cancer patients. Therefore, the development of more effective therapies for treating triple negative breast cancer is a high priority for clinical research. The overall objective of our proposed studies is to advance the understanding of the molecular underpinnings of triple negative breast cancer and to evaluate targeted therapies for treating this disease. Specifically, our studies will examine the utility of targeting cell cycle checkpoints and the phosphoinositol-3-kinase (PI3K) signaling pathway in triple negative breast cancers. We will utilize a novel mouse model that we have named HAMLET for Human and Mouse Linked Evaluation of Tumor. In this model, human breast cancer specimens that are triple negative are engrafted and passaged in the mammary glands of immunodeficient mice. A major advantage of the HAMLET model, over other models that currently exist, is the high degree of concordance between the tumor established in the mouse and the original human cancer. Thus, our proposed preclinical studies are expected to be particularly relevant to the clinical situation. Additional advantages of the HAMLET model include: availability of sufficient quantities of pre- and post-therapy tumor for analyzing pathways disrupted in the original, pre-treatment tumor and for carrying out biomarker studies that validate target specificity of the treatment. In addition, this model can be used to optimize treatment strategies; evaluate more selective protein kinase inhibitors; evaluate different combinations of DNA damaging agents and protein kinase inhibits; and carry out properly controlled clinical trials in mice. The studies outlined in our proposal will provide the foundation for the design of future clinical trials focusing on targeted therapies for treating triple negative breast cancers.