The grant is for Dr. Lamb’s study “DNA Repair Deficiencies in Infertile Men and Cancer Risk” for a project period of Aug. 1, 2024-April 30, 2029. The study will define the molecular links between male infertility and their increased risk of serious diseases, such as cancer.

As Dr. Lamb explains, there is a need to identify the causes of the most severe form of male infertility, non-obstructive azoospermia (NOA), where there is spermatogenic failure resulting in an ejaculate with no sperm.

“NOA men have an increased risk of serious diseases, such as cancer, when compared with fertile men or men with sperm in their ejaculates. However, the common link between their infertility and their increased disease risk has remained elusive,” explains Dr. Lamb.

The Lamb lab works on the molecular basis of NOA, specifically defects in DNA/mismatch repair proteins. She is using the results of previous research to focus her attention on defining the cancer risks of men with NOA and to look for common genetic/epigenetic links between men’s infertility and their health risk.

The study will look into the mismatch repair (MMR) proteins and MutS homolog 5 (MSH5), which are involved in DNA repair and meiotic recombination, a process that occurs during meiosis when homologous chromosomes in a cell exchange DNA segments with each other. MMR-deficient cells often have many DNA mutations that can lead to cancer.

For this study, Dr. Lamb and her team will use databases of expertly characterized NOA men from three institutions which includes ~14,200 NOA/severely oligozoospermic men (men with low sperm count) and more than 56,600 infertile men. Their profiles will be matched to the national Virtual Pooled Cancer Registry in the U.S. and the Canadian Cancer Registry.

“We will test the hypothesis that the decreased mismatch repair and/or MSH5 expression in a subset of infertile men leads not only to decreased genetic stability, impaired DNA break, and defective homologous recombination but also leads to the development of malignancies and NOA,” said Dr. Lamb.

As Dr. Lamb explains, these investigations are important because there are associated health issues for azoospermic men - those whose ejaculate contains no sperm - but frequently infertile men are never evaluated when couples are treated by in vitro fertilization and intracytoplasmic sperm injection (ICSI).

“(In the future) these men could be advised of their potential health risks associated with their infertility. They can be closely followed for cancer development,” said Dr. Lamb. “Earlier intervention may improve their outcomes.”

Co-investigators on the study include Keith Jarvi, MD, Ethan Grober, MD, Kirk Lo, MD, and Christopher Wallis, MD, all from Mount Sinai Hospital in Toronto, Mark Sigman, MD, and Gabriella Avellino, MD, from Rhode Island Hospital, Andrew Vickers, PhD (Memorial Sloan Kettering Cancer Center), Peter Schlegel, MD (New York Men’s Health Medical), James Kashanian, MD, Marc Goldstein, MD, Kevin Kensler, ScD, from Weill Cornell Medicine.

Please join us in congratulating Dr. Lamb and her team!

The mission of Alex’s Lemonade Stand Foundation is to change the lives of children with cancer through funding impactful research, raising awareness, supporting families, and empowering everyone to help cure childhood cancer. The funds for this Catalyst award were made possible thanks to passionate advocacy of the local Alex’s Lemonade Stand, including the generous support of the annual ALSF Lemon Mixer in Kansas City. To date, the Kansas City ALSF Lemon Mixer has helped raise more than $185,000 for pediatric cancer research initiatives at Children’s Mercy.

The funding will help Dr. Iwakuma’s project titled “Identifying Drugs That Specifically Kill MDM2-Overexpressing Pediatric Cancers” by helping to purchase a multifunctional plate reader. The piece of equipment is essential for Dr. Iwakuma and his team to be able to perform screening and validation.

Osteosarcoma is a type of bone cancer that begins in the cells that form bones. As Dr. Iwakuma explains, combinational treatment of surgery and chemotherapy improve 5-year survival rate of children and adolescent patients. However, prognosis of high-grade osteosarcoma patients with macrometastasis and recurrence remains poor with the long-term survival below 20%. To overcome this poor prognosis, researchers must learn about the genetics and molecular pathogenesis of osteosarcoma and identify the vulnerabilities.

Several mutations and genetic abnormalities are found in osteosarcoma. Of these, abnormalities in the tumor suppressor p53 (p53) is one of the most frequent events in osteosarcoma, which is well-correlated with poor outcome in patients. The p53 activity is mainly regulated by an oncogene MDM2 which acts as the major E3 ubiquitin ligase for p53 to induce p53 degradation. MDM2 is overexpressed in ~30% of human osteosarcoma. Although overexpressed MDM2 inhibits p53 activity and promotes cancer progression, increasing evidence indicates that MDM2 has p53-independent cancer-promoting activities. However, no drug that inhibits p53-independent MDM2 function is clinically available.

“Such a drug would significantly improve prognosis of patients with osteosarcoma and other pediatric cancers that overexpress MDM2, including rhabdomyosarcoma and Ewing sarcoma,” said Dr. Iwakuma.

The goal of Dr. Iwakuma’s study is to identify clinically available drugs that specifically kill MDM2-overexperessing cancer cells. He hopes to also discover a new p53-independent function of MDM2, which could provide novel therapeutic targets for these MDM2-overexpressing cancers as novel vulnerabilities.