Toward Novel Therapeutics for TSC and LAM: Using Mechanisms of a Bacterial Protein to Sensitize Cells to Rapamycin
Abstract
The long-term goal of the proposed research is to facilitate the development of new treatments for tuberous sclerosis complex (TSC), lymphangioleiomyomatosis (LAM), and other diseases that are due to malfunction of the same cell processes. The basis for the proposed research is that we have discovered a protein (called OspB) produced by bacteria and not by human cells that has the ability to make human cells more responsive than normal to rapamycin and its analogs, including sirolimus and everolimus. Rapamycin and its analogs are one of the mainstays of current therapy for TSC and LAM. Compounds that sensitize cells to rapamycin have never been described previously, which indicates that the discoveries that arise from the proposed research have the potential to open up an entirely new avenue for drug discovery for these diseases. The goal of the proposed research is to determine how OspB makes cells more sensitive to rapamycin and its analogs. Understanding how OspB makes cells more sensitive to these drugs will enable us and other scientists to rationally develop new drugs that have the potential to improve treatment for TSC, LAM, and related diseases. New drugs developed based on these discoveries have the potential to avoid undesirable effects of rapamycin and its analogs that limit their use. As OspB appears to act only on the cellular pathway that malfunctions in TSC and LAM (mTORC1) and not on the related pathway that functions properly in these diseases (mTORC2), drugs developed based on our discoveries have the potential to only target the malfunctioning pathway and therefore to avoid a major side effect of rapamycin treatment, which is due to targeting of the related pathway that functions normally. The potential risks would primarily be side effects due to this new class of drugs. As for most discoveries that have the potential to fundamentally change the course of disease treatment, we anticipate that the time frame for discovery of such new drugs would be approximately 5-10 years after we determine how OspB sensitizes cells to rapamycin inhibition of the malfunctioning pathway; although not immediate, the impact has the potential to be enormous.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710314
Entities
People
- Marcia B Goldberg
Organizations
- Massachusetts General Hospital
- United States Army