Having lost her mother to cancer, Zhanna Kovaleva is passionate about cancer research and helping cancer patients. She has been investigating pancreatic cancer for the past two years and, through her mentor, has learned about different aspects of the disease that she may not have studied in her classes. Zhanna encourages students to start thinking about research early and to be aware that it is an immense time commitment. In the future, she plans on becoming a medical oncologist, while continuing to engage in research. Zhanna is a member of the Russian and Hillel clubs and volunteers at the Hollywood Sunset Free Clinic. In 2004, she will be the Head Coordinator for UCI’s Biology of Cancer course.

The increased biological aggressiveness in pancreatic ductal adenocarcinoma (PDAC) is due to numerous molecular alterations, including the presence of Smad4 mutations and overexpression of transforming growth factor beta (TGF-b) isoforms. There is strong evidence that the overexpression of TGF-bs is associated with decreased patient survival. This study examined the possibility of abrogating the TGF-b-Smad4 pathway. BxPC3 clones expressing wild-type Smad4 were established using the Smad4-null BxPC3 pancreatic cancer cell line. Then using techniques such as immunoblotting, Northern blot analysis, and nude mouse tumor formation assays, significant inhibition of tumor growth was shown in BxPC3 cells expressing Smad4 clones compared to BxPC3 cells devoid of Smad4. As a second approach to testing the hypothesis, soluble type II TGF-b receptors (sTbRII) were purified and unfolded using affinity chromatography, and the biological activity of the sTbRII was measured by performing a colometric assay. The data showed that purified sTbRII has the ability to neutralize TGF-b1 actions in vitro. Therefore, it is believed that restoring Smad4 functions and using sTbRII will lead to the suppression of pancreatic cancer cell growth in vivo, and that these approaches will lead to the development of novel therapeutic strategies in PDAC.

Murray Korc College of Medicine

Pancreatic cancers overexpress multiple growth factors, including transforming growth factor-beta (TGF-b) isoforms. This cancer is resistant to TGF-b-mediated growth inhibition because the cells harbor Smad4 mutations, overexpress Smad6 or Smad7, and underexpress the type I TGF-b receptor, resulting in loss of negative growth constraints. Ms. Kovaleva, working with her colleagues, demonstrated that it is possible to fix this “broken brake,” raising the prospect for novel therapeutic interventions. It was sheer pleasure to work with her, guide her, see her knowledge of cancer biology and the scientific process grow and mature. Her dedication and motivation reinforced my own desire to do more, underscoring the two-way street of beneficial interactions between mentor and student. Thank you Zhanna!