An increased incidence of many different cancers is a major hallmark of aging. The Lombard group is interested in elucidating links between cancer and aging, using cellular and mouse models, coupled with detailed analysis of cellular metabolism via Seahorse and mass spectrometry-based metabolite measurements. Their long-term goal is to gain new insights into cancer and aging, with the possibility of developing new mechanism-based therapeutics to slow the aging process and delay the onset of cancer.

The Lombard group is currently pursuing projects in the following areas:

• SIRT5 as a novel therapeutic target in cancer: A major focus of the Lombard lab is the sirtuins, a family of protein deacylases that regulate chromatin, metabolism, carcinogenesis, and lifespan. Sirtuins remove acetyl and other acyl moieties from their targets, thereby regulating their biological activities. The lab applies biochemical, cellular, metabolic, and mouse genetic approaches to address key questions in sirtuin biology. A major current focus of the Lombard group is SIRT5, a sirtuin that removes non-canonical modifications from its targets: succinyl, malonyl, and glutaryl moieties. Dr. Lombard’s group has found that SIRT5 is dispensable in normal mice, but critical to survival of specific cancer types, including melanoma and the pediatric cancer, Ewing sarcoma, via chromatin regulation (JCI, 2021). They have carried out a large-scale proteomic identification of SIRT5’s targets (Mol Cell, 2013). In collaboration with medicinal chemists, they are generating potent and selective SIRT5 inhibitors, as tool compounds and candidate novel cancer therapeutics (Eur J Med Chem, 2022). These efforts have led the Lombard lab to pursue other projects related to targeting chromatin for melanoma therapy. The lab has also recently shown that SIRT5 is cardioprotective in the context of pressure overload, via suppression of cardiac fibrosis (Sci Rep, 2022).
  
  
• Targeting the aging process with small molecules: Another major interest of the group is targeting stress resistance and aging via small molecules. The lab recently published a large collaborative project to identify small molecules that promote stress resistance in mammalian cells, and increase longevity in C. elegans and Drosophila, to prioritize compounds for lifespan testing in mammals (Sci Adv, 2020). These efforts nominated cytoprotective Nrf2/SKN-1 signaling as a pathway meriting further study in this regard. It has also led to efforts to elucidate novel links between heavy metal-mediated toxicity and epigenetic dysregulation. Another ongoing project in this general area involves PAPP-A, a protease that regulates IGF signaling and lifespan. The lab is attempting to understand in greater depth how PAPP-A functions, and in collaboration with medicinal chemists, to develop small molecule PAPP-A inhibitors as candidate anti-aging therapeutics. More generally, the lab is developing screening approaches to nominate potential anti-aging drugs for further study.