Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Family Alliance
c/o VHL Family Alliance, 2001 Beacon Street, Suite 208, Boston, MA 02135-7787
+1-617-277-5667 ext. 709 or +1-888-340-4415 ext. 709
hlrcc@vhl.org
Vikas P. Sukhatme, MD, PhDTitle of Proposed Project: LDH-A inhibitors for the treatment of fumarate hydratase (FH) associated leiomyomatosis and renal cell cancer (HLRCC |
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Description of Project in lay terms:
People with HLRCC have an alteration in one copy of the fumarate hydartase (FH) gene. In cells where the function of the second copy of FH is altered, cell growth goes out of control and a tumor may form. Thus the tumor cells have both copies of the FH gene out of order, while the healthy cells continue to have one working copy of the FH gene. We want the healthy cells to live; we want the tumor cells to die so we can shrink or eliminate the tumor. The challenge is to target only the tumor cells, not the healthy cells.
When both copies of FH are altered, this can cause an alteration in a process called the TCA cycle, or the Krebs cycle. In order to live, the cell must metabolize glucose into pyruvate. In a healthy cell, pyruvate can either be fermented into lactate, or can be sent through the Krebs cycle to boost its energy. When both copies of FH are out, the Krebs cycle does not work, and all pyruvate is fermented into lactate. This gives us an opportunity to sort out which cells are healthy and which are tumor cells (forming only lactate).
The critical enzyme in the process of fermentation glycolysis is LDH-A. Our goal in this project is to determine whether blocking this LDH-A enzyme will result in the death or at least the inhibition of cell growth of the tumor cells. We will first inhibit the activity of FH to simulate the state of HLRCC tumor cells, and then assess whether blocking LDH-A has a detrimental effect on the survival and proliferation of tumor cells. In the latter part of this project we will aim to find drugs that interfere with the activity of the LDH-A enzyme, thus setting the stage for developing a therapy for treating tumors of HLRCC.
Scientific Summary of Project:
HLRCC patients develop leiomyomas of the skin and uterus as well as invasive kidney cancers. The genetic basis for HLRCC is felt to be a germline inactivating mutation in the gene for the TCA cycle enzyme FH. In addition, a second FH mutation in leiomyomas and in kidney tumors has been noted. Since FH is a critical enzyme in the TCA cycle that converts fumarate to malate, inhibition of this process should necessitate that glycolysis followed by fermentation of pyruvate to lactate will be required to provide ATP as well as to regenerate NAD +. This hypothesis will be tested in this proposal. In fact, it has recently been shown that FH deficiency leads to upregulation of HIF1α and that targets for HIF1α, such as lactate dehydrogenase-A (LDH-A), have been found to be increased in tumors of patients with FH. LDH-A is of particular interest because it is involved in pyruvate lactate interconversion. Therefore, our aims will be as follows.
In Aim 1 we will test the fundamental hypothesis of this proposal, that is whether the LDH-A is blockade in the background of a partial FH blockade results in diminution either of cell survival or proliferation. In Aim 2, we will explore the intracellular mechanisms that are responsible for the effects on cell survival or proliferation. In Aim 3, we will initiate a structure based in silico screen for LDH-A inhibitors.
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