Dharini van der Hoeven, Ph.D.

Areas of Interest

Research Interests

Research Information

Cell signaling in cancer & discovery of anticancer therapeutics

Dr. van der Hoeven’s research focuses on characterization of signaling mechanisms in cancer and identification of novel anti-cancer therapeutics, with emphasis on Ras proteins.Ras proteins play an essential role as molecular switches controlling cell proliferation, differentiation, and survival.They are small GTPases that reside on the inner leaflet of the plasma membrane, linking extracellular signals through membrane receptors to intracellular signals. There are three isoforms, H-, N-, and K-Ras, which oscillate between an active GTP-bound and inactive GDP-bound state; GTP-Ras then promotes the activity of a wide range of effector kinases and related signaling enzymes (Figure 1). Mutations that result in constitutive activation of the Ras proteins are found in 20% of all human tumors, including head and neck cancers. Such activating mutations have been reported in all three isoforms but the major clinical problem is K-Ras, making this isoform an important target for the development of anticancer drugs.

One facet of Dr. van der Hoeven’s studies involves identification of novel chemical entities that selectively block the K-Ras protein. K-Ras must associate with the plasma membrane to be active. Therefore, blocking plasma membrane targeting would be beneficial in preventing signal output from oncogenic K-Ras. In collaboration with Dr. John Hancock at The University of Texas Medical School at Houston, using a high-content cell-based screening assay, she has identified novel compounds that act as specific inhibitors of K-Ras plasma membrane targeting with no detectable effect on the localization of H- and N-Ras (Figure 2). Extensive characterization of one such compound, fendiline hydrochloride, has shown that it significantly inhibits signaling downstream of constitutively active K-Ras, and blocks proliferation of pancreatic, colon, lung, and endometrial cancer cell lines expressing oncogenic mutant K-Ras.Dr. van der Hoeven’s current research is focused on using these inhibitors of plasma membrane targeting of K-Ras as tools to dissect the mechanisms of K-Ras trafficking and membrane binding, and to develop novel, potent anti-K-Ras drugs.Another major aspect of her studies involves exploring the use of novel K-Ras inhibitors as chemotherapeutic agents in combination therapy.Novelinhibitors of plasma membrane targeting of K-Ras such as fendiline could be used in combination chemotherapy and potentially be a promising therapeutic strategy for treating aggressive malignancies.