Accute Myeloid Leukemia (AML)
Establish diagnostic tools for identifying cancer patients vulnerable to UGT1-related resistance and develop small inhibitors of this resistance mechanism
|Principal Investigator||Katherine Borden|
Drug resistance is the major reason for failure of cancer treatment with drugs. Resistance may be either pre-existent (intrinsic resistance), or induced by drugs (acquired resistance). The mechanisms by which resistance is achieved are complex and vary depending on specific cancers and treatments. Understanding how cancer cells that were once killed by drugs develop resistance is important for developing new cancer treatments. We have identified a novel mechanism for resistance exhibited in Acute Myeloid Lymphona (AML) patients. Patients who initially responded to the drug (ribavirin) eventually developed resistance. This was due to modification of the drug by a family of proteins called UDP-glucuronosyltransferases (UGTs), which were found to be highly abundant in resistant cells. The same mode of resistance was also detected for other drugs used to treat cancers, such as araC and azacitidine. We aim to determine how wide spread this type of resistance is by monitoring the abundance of UGTs in a large array of AML specimens and in other cancer subtypes. We will also develop drug candidates to fight this mode of resistance by screening UGT proteins using Nuclear Magnetic Resonance methods against a fragment library of small molecules. Our overall goal is to identify cancer treatments and patients most likely to develop this new form of resistance mechanism and ultimately overcome this resistance with therapeutic agents identified from the small molecule NMR screen.