"We are hoping this is something that we can repurpose quickly for those affected by these variants,” says Heather Christofk, PhD.
Investigators have found that inhibition of the purine salvage pathway in hereditary leiomyomatosis and renal cell cancer (HLRCC) tumors reduced growth of the tumors in vivo, signaling a possible new treatment strategy for patients with kidney cancer, according to findings published in Cancer Discovery.1,2
The use of 6-mercaptopurine, which targets the purine salvage pathway, led to a reduction in the number of nucleotides and tumor growth.
The targeting of this pathway is based on the study findings that a number of genetic variants previously of unknown significance rely on the purine salvage pathway for growth, and they predispose patients to HLRCC, which increases the risk of developing aggressive kidney cancer.
“Based on these findings, not only can we now better characterize a lot of patients who have a variant and did not previously know if they really had an increased risk of kidney cancer, we can possibly repurpose this well-tolerated drug to be a rapidly translatable treatment strategy. And we are hoping this is something that we can repurpose quickly for those affected by these variants,” said senior author Heather Christofk, PhD, in a news release on the findings.2 Christofk is the director of basic and translational research at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center.
For the study, the investigators assessed the activity and level of fumarate present among 74 variants of the fumarate hydratase gene that were previously of unknown significance. Among those, over half were found to be inactive and likely contributing to growth of the disease.
Cells lines of fumarate hydratase gene variants of varying degrees of activity were then assessed, showing different levels of fumarate. Upon analysis, the investigators uncovered that an accumulation of fumarate due to fumarate hydratase deficiency disrupts pathways for cell growth, causing the cells to rely on the purine salvage pathway for proliferation instead.
“One way to stop tumor growth from occurring, is to potentially target this pathway. We found that these tumors rely on this alternative pathway, which uses nutrients from the environment in order to synthesize nucleotides. Generating nucleotides is essential for the tumor cells to replicate and sustain growth,” explained lead author Blake Wilde, MD, in the news release.2 Wilde is a postdoctoral fellow in the Christofk laboratory at UCLA.
When the investigators analyzed the response of cell cultures and mice to the use of 6-mercaptopurine, which targets the purine salvage pathway, they found that the drug led to a reduction in the number of nucleotides and tumor growth.
The authors concluded, “These findings suggest pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.”
References
1. Wilde BR, Chakraborty N, Matulionis N, et al. FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer. Cancer Discov. Published online May 31, 2023. Accessed July 19, 2023. doi:10.1158/2159-8290.CD-22-0874
2. Gene mutations linked to hereditary kidney cancer predisposition but potential Achilles’ heel identified. News release. University of California, Los Angeles (UCLA), Health Sciences. July 12, 2023. Accessed July 19, 2023. https://www.newswise.com/articles/gene-mutations-linked-to-hereditary-kidney-cancer-predisposition-but-potential-achilles-heel-identified?sc=mwhr&xy=10016681
Adding nivolumab to low-dose tivozanib does not improve PFS in renal cell carcinoma
July 19th 2024"While the addition of an ICI to low dose FOTIVDA did not improve PFS outcomes after prior ICI, we consider the control arm data an important, evidence-based and clinically meaningful contribution to the oncology community treating relapsed or refractory advanced RCC following front-line ICI combinations," says Michael P. Bailey.
Live bacterial supplementation may improve TKI-based treatment efficacy in kidney cancer
June 30th 2024CBM588 could be exciting in cancer treatment because of its potential to enhance the efficacy of immune checkpoint inhibitor-based treatment, improve patient outcomes, and modulate the gut microbiota in beneficial ways,” says Sumanta Pal, MD.
Pembrolizumab/lenvatinib labels updated to include KEYNOTE-B61 data in non-ccRCC
June 28th 2024"The addition of efficacy data from the KEYNOTE-B61 trial reinforces the important role of KEYTRUDA plus LENVIMA as a frontline treatment option for adult patients with advanced RCC regardless of histology," says Takashi Owa, PhD.