Molecular Targets & Therapeutic Resistance Program
As a basic science research program, the immediate goal of Molecular Targets & Therapeutic Resistance (MTTR) is to design and advance a comprehensive research agenda integrating investigations in basic cancer biology, biochemistry, and molecular and cellular biology to improve our understanding of the mechanisms of therapeutic resistance (including responses to radiation, chemotherapy agents, and hormonal agents) in tumor and normal cells. The ultimate goal is to apply the basic knowledge gained from these studies, primarily through interactions with the 3DT Program, but also with other Lombardi programs, to improve therapeutic interventions. The MTTR program is neither target/pathway or tumor-type specific. Current research projects include areas such as radiation-induced alterations in mitogenic signaling; molecular and chemical targeting for sensitization of cancer cells to radiation, chemotherapy agents, and hormonal treatments; functional analyses of the role of poly (ADP-ribose) polymerase (PARP) activation in apoptosis and transcriptional regulation; pathways of radiation-induced stress response, mechanisms of radiation resistance; global analyses of gene expression coupled with proteomics studies to identify determinants of therapeutic resistance; and mechanisms of DNA damage processing. The use of radiation, chemotherapeutic drugs and hormones in these studies is ultimately related to the effects of "oxidative stress" and/or of "free-radicals", which from a mechanistic perspective provide an integrative focus to the MTTR program. The Specific Aims are:
Aim 1: To characterize the mechanisms of resistance to ionizing radiation, chemotherapy, and hormonal therapy
Aim 2: To identify therapy resistance-inducing molecules and pathways that may be targeted for therapeutic gain.
Aim 3: To develop approaches for overcoming therapy resistance.
Aim 4: To understand the mechanisms by which radiation and oxidative stress cause malignant transformation.
The overall conceptual framework of the MTTR Program is based on the idea that signaling abnormalities in cancer are the same defects that affect responses to conventional treatments. Thus cytotoxic agents used in cancer treatment (ionizing radiation, chemotherapy and hormonal therapy) often work by inducing or inhibiting specific signaling events rather than by causing random and non-specific cytotoxicity. For example, our understanding of how ionizing radiation works has changed dramatically from considering it an agent that would kill cells by causing random, massive DNA structural alterations, to a "signal" that would turn on/off specific transduction pathways and activate/repress the expression of specific gene repertoires. It is now established that the nature and magnitude of the effect of therapeutic agents on specific components of the cellular machinery other than DNA may determine the resistance or sensitivity of the cells to treatment. Thus, an important research goal in MTTR is to identify signaling molecules and pathways controlling the sensitive/resistant cellular phenotype. Understanding these signaling and gene expression circuits may permit the sensitization of naturally resistant cells/tumors as well as the optimization of treatment protocols in the future, to maximize therapeutic gain. Furthermore, this concept has evolved to consider that, while targeting individual molecules may be sufficient to inhibit tumor growth, simultaneous targeting of more than one molecule/pathway may be required to attain tumor regression responses.
The hypothesis shared by research projects in the MTTR Program is that modulation of the expression and/or activity of molecules/pathways that are key determinants of the intrinsic resistance of tumor cells to radiation, chemotherapy, or hormonal treatment, may result in sensitization of cancer cells to treatment and lead to improved outcomes.