Grant: Strategic Projects - Group

Conventional anti-cancer therapies target a common feature of cancer cells - their ability to divide. Conventional therapies equally kill cancer and normal dividing cells; moreover, they are only 5-6 times less cytotoxic to normal non-dividing cells. As a result, conventional therapies have debilitating side effects (e.g. severe indigestion, hair loss, and cytopenias) and the dose required to eradicate tumors often exceeds the lethal dose. In the last two decades, a significant progress has been made in understanding the molecular bases of cancer. Many abnormal proteins, which initiate and drive the disease, have been identified and can now be usec as therapeutic targets for so-called mechanism-based therapies. Simply speaking, mechanism-based drugs kill only cells in which the therapeutic target is active leaving all other cells intact. The ratio between the therapeutic dose and lethal dose can be greater than one hundred, making mechanism-based therapies very safe There is a downside, however: the efficacy of any given mechanism-based therapy is lower than those of conventional therapies. Malignant tumors are highly heterogeneous; they consist of clones (subpopulations) of cells with different abnormal proteins. Some of these clones are likely to be resistant to a highly specific therapy that targets only one protein. To cure cancer, the resistant clones have to be identified along with their therapeutic targets and another therapy has to be used to eliminate mem. Thus, the efficient use of mechanism-based therapies requires two diagnostic procedures: (i) assessment of tumor heterogeneity with respect to the presence of multiple therapeutic targets and (ii) monitoring the heterogeneity of tumor response to the therapy at the molecular level. A technology for carrying out these procedures is analytically challenging and currently unavailable. Here we propose to develop a technology termed aptamer-mediated analysis of proteins in individual cells (AMAPIC), which will facilitate the efficient use of mechanism-based anti-cancer therapies.