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    Pre-Clinical Evaluation of Novel Hsp90 Inhibitors in Breast Cancer

    Scientific Abstract:
    Pre-Clinical Evaluation of Novel Synthetic Hsp90 Inhibitors in Breast Cancer A recent trend in cancer therapy has been to develop agents that “target” a single molecular alteration. These efforts have led to the development of novel therapies such as Herceptin which has been successful for the fraction of breast cancer patients with tumors dependent on Her2. However, most tumors are characterized by multiple growth regulatory alterations and these are tumor-type specific. It has been suggested that one potential way to circumvent this problem is to target the machinery that allows most breast cancer cells to function with the abnormalities they carry: the chaperone Hsp90. We have developed and validated a new generation of potent agents that by specific inhibition of tumor Hsp90 can target a broad-range of breast cancers. These are small molecules with improved pharmacological profiles over 17AAG, the Hsp90 inhibitor now in Phase I/II clinical trial, and have been discovered and developed by our group. One of the initial leads, PU24FCl, exhibits multiple anti-tumor-specific effects such as degradation of Hsp90-client proteins involved in cell growth, survival and specific transformation, inhibition of cancer cell growth, delay of cell cycle progression, induction of morphological and functional changes and apoptosis via selective and potent inhibition of the chaperone. In concordance with its higher affinity for tumor Hsp90, in vivo PU24FCl accumulates in tumors while being rapidly cleared from normal tissue. Concentrations achieved in vivo in tumors lead to single agent anti-tumor activity at non-toxic doses. Further chemical optimization efforts of PU24FCl have resulted in agents with higher potency and improved solubility. In the proposed investigation, we aim to characterize the biologic effects of six such inhibitors on breast cancer cells and to study lead compounds selected in Aim 1 using xenograft models of breast cancer. The toxicities, including the dose-limiting toxicity, antitumor activity and effects on Hsp90 client proteins in tumors will be determined. Breast carcinomas selected for analysis include:tumors with defective Rb function or expression, tumors with overexpression of Her2, tumors regulated by the Raf-1/MAPK pathway and tumors with defective PTEN. The lead compounds will be analyzed for both single agent activity and also in combination with taxol and doxorubicin. The long term goal of this endeavor is the rational clinical translation of a drug working by such mechanisms in the treatment of patients with advanced breast cancer.

    Lay Abstract:
    Pre-Clinical Evaluation of Novel Synthetic Hsp90 Inhibitors in Breast Cancer Human cancer is characterized by genetic instability leading to the amplification or mutation of oncogenes. These genetic alterations may inhibit apoptosis, lead to dysregulated growth or enhance metastatic potential. A number of genetic alterations responsible for the malignant phenotype have been identified and a trend in cancer therapy over the past 10 years has been to develop agents that “target” a single molecular alteration. These efforts have advanced the development of novel therapies such as Gleevec and Herceptin that have been successful for the small fraction of patients with tumors dependent on the oncoproteins they target. However, since most tumors are characterized by multiple growth regulatory alterations, targeting one abnormality is insufficient. In addition, as the growth regulatory alterations are cell-specific, a drug targeting one abnormality will be limited to use in only a subset of cancers. Identifying the subset of responsive tumors has been difficult in clinical trial settings and many drugs have failed due to inadequate patient selection. Further, the genetic plasticity of cancer cells often permits rapid development of resistance, even in patients who initially respond to targeted agents such as Gleevec or Herceptin. It has been suggested that one potential way to circumvent this problem is to target the machinery that allows most cancer cells to function with the abnormalities they carry: the molecular chaperone Hsp90. Unfortunately the currently available Hsp90 inhibitors have not lived up to the promise of their target. Difficulty of administration as well as secondary toxicities unrelated to Hsp90 inhibition, result in their problematic clinical use. We have developed novel inhibitors of Hsp90 with improved drug qualities. These agents have potent anticancer activities in both in vitro and in vivo models of breast cancer and show at least one-log selectivity for cancer cells versus normal cells. In this proposal, we plan to further develop these agents and design rational strategies for their future clinical use. Due to a general and wide-ranging targeting of oncogenic transformation and to their improved “drug-like” qualities, these agents represent compelling new therapeutics. The long-term goal of this work is the phase I trial of a selected lead compound in patients with advanced breast cancer.