Welcome! A bit of background on what we do in the Shapiro Lab.

Small Molecule Biomodulators for Studying and Treating Diseases
Our focus is on the discovery and use of novel small molecule biomodulators that serve as probes to identify and analyze interactions and pathways important in cancer and in the development of these small molecules as potential anticancer drugs. Classically, a new pathway related to cancer was identified and proposed as a potential drug target, and in subsequent studies a lead small molecule inhibitor might be identified. Our approach is exactly the opposite. We start with unbiased screening to generate a large data set from which we choose a lead small molecule inhibitor whose properties in simple follow on assays suggest it is likely to exhibit an unexplored mode of action.  Then we progress from identification of the inhibitors mode of action to the relation of that action to previously undescribed normal actions of its target. Our successful application of this approach to pathways of estrogen receptor action and therapeutic candidates in breast and ovarian cancer demonstrates the potential of our approach.

The Molecular Biology of Steroid Hormone Action
The effects of steroid hormones, such as estrogens, testosterone and other androgens, progesterone, thyroid hormone, retinoids, Vitamins A and D, bile acids and oxygenated cholesterol derivatives are mediated by binding of these small molecules to specific receptor proteins called steroid/nuclear receptors. This large-superfamily of gene regulatory proteins is the fundamental system for ligand-regulated gene transcription in multicellular eukaryotes.

Estrogen and Androgen-dependent Breast, Ovarian and Prostate Cancer
In addition to their roles in growth and differentiation in normal cells, steroid hormones play critical roles in cancer and other human diseases. Acting through the estrogen receptor (ER), estrogens play a key role in the growth and metastases of most human breast cancers. Testosterone, acting through the androgen receptor (AR), plays a key role in growth of both primary and recurrent prostate cancers. Treatment of breast and prostate cancer involves inhibiting hormone production and the use of small molecules, such as tamoxifen, that compete with the normal hormones for binding to the receptor. Although effective initially, the tumors eventually develop resistance to these therapies and the tumors return and resume growth. Although most ovarian and uterine cancers are ER positive, treatment with tamoxifen and other competitor antiestrogens is usually ineffective and approximately two-thirds of ovarian cancer patients die within 5 years. Breast, ovarian cancer and prostate cancer currently kill ~42,000, ~15,000 and ~23,000 Americans each year, respectively. An important goal of our research is to identify new small molecule inhibitors of ER and AR action in breast and prostate cancer that bypass the sites targeted by current drugs and are effective against tumors that are resistant to current therapies.

Targeting mRNA in Cancer
Small RNAs, including microRNAs and siRNAs play important roles in controlling mRNA and proteins levels, and are often disregulated in cancer. However, they have not been targeted successfully using small molecules. IMP-1/IGF2BP1/CRD-BP is a multifunctional mRNA binding protein that works in part by transducing signals from microRNAs. IMP-1 is a major regulatory target of the let-7 microRNAs that are often down-regulated in human cancers. IMP-1 is an oncofetal mRNA binding protein that binds to and stabilizes the mRNAs encoding c-Myc and other oncogenes and multidrug resistance protein 1 (MDR1), and increases activity of the tumor-enabling factor NF-kB. Elevated expression of IMP-1 is associated with a poor prognosis in human cancers. We are working to understand IMP-1 action and to develop the first small molecule biomodulators of this class of mRNA binding proteins.