An NCI-designated Comprehensive Cancer Center

Linda Malkas, Ph.D.

Dean, Translational Science, External Affairs; M.T. & B.A. Ahmadinia Professor in Molecular Oncology
Research Focus
  • Cancer biology
  • Peptides directed against cancer associated PCNA has therapeutic potential in breast cancer
  • New molecular target for neuroblastoma therapy
  • NIH/NCI Cancer Center Support Grant
  • A structure/function analysis of a tumor specific protein
  • caPep: mechanistic evaluation of an agent for neuroblastoma
  • Development of novel agents, technologies, and markers for the better diagnosis, prognosis, screening, prevention and treatment of breast cancer
Appointments
Professor and Associate Chair, Department of Molecular and Cellular Biology
I have expertise and an established track record in the areas of human cell DNA replication/repair, and cancer cell biomarker and therapeutic target discovery. I am currently a professor and associate chair of the Department of Molecular and Cellular Biology at Beckman Research Institute of City of Hope and dean, Translational Science, External Affairs. In 2017, I was appointed to the governing board of the California Institute for Regenerative Medicine (CIRM). I co-founded and currently co-lead the Molecular Oncology Program at the cancer center.
 
My laboratory has focused on elucidating the mechanisms underlying cancer cell DNA damage accumulation, which has also been correlated with disease progression. Our laboratory was the first to successfully isolate an intact multiprotein DNA synthesis complex that is both stable and fully functional, (termed the DNA synthesome), from a variety of mammalian cell lines and tissues. Subsequent work demonstrated that the synthesome of malignant  epithelial cells has a significantly decreased DNA synthesis fidelity, (exhibiting a more error-prone synthesis process), than the complex of nonmalignant  epithelial cells. We demonstrated that this occurs in intact epithelial cells as well. We also showed that nonmalignant human  cell transformation to a malignant state is accompanied by an alteration of a specific protein component of the synthesome, namely proliferating cell nuclear antigen (PCNA). Different isoforms of PCNA that display both acidic and basic isoelectric points (pI) have been demonstrated. These analyses also revealed that an additional acidic form of PCNA was highly expressed in cancer cells (referred to as the cancer-associated PCNA or caPCNA). An antibody was developed to caPCNA that proved to be highly selective for this isoform in cancer cells.
 
In the course of our studies, we have identified a small caPCNA related peptide (caPeptide), as well as small molecule compounds targeting caPCNA, that promote cancer cell cytotoxicity with great specificity. These agents have the potential ability to block the binding of several cellular proteins that participate in DNA replication, repair, cell cycle control, transcription and chromosomal recombination in cancer cells. The binding of full length caPCNA to the proteins mediating these processes is disrupted when the caPeptide or small molecule compounds are allowed to compete with these proteins for their naturally occurring binding site on caPCNA. This disruption in the function of vital cellular processes would render caPeptide or small molecule compounds cytotoxic by themselves, or in combination with other agents, such as, DNA damaging cancer chemotherapeutic drugs. These agents, either alone or in combination with other cancer therapy agents are potentially useful cancer chemotherapeutics or augmentors of the pharmacodynamic effect of specific anti-cancer chemotherapeutics.

 

 

Locations

City of Hope Comprehensive Cancer Center, 1500 East Duarte Road

Duarte, CA 91010

In The News
 
 
An Expert's Voice
City of Hope News

City of Hope’s 15th annual Songs of Hope to recognize Boi-1da, Marc Shaiman, Diane Warren, Tierra Whack, Hayley Kiyoko, the Dream, Linda Malkas, Ph.D., and more

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