Scholars / Targeted Therapies

Understanding of what proteins drive cancer is critical and such advances will lead to cures.

Yousef Alharbi

Working in the laboratory of Dr. Manish Patankar studying novel chemotherapy drugs for women with advanced ovarian cancer.

Yousef studies the molecular mechanism of two novel chemotherapeutic drugs that inhibit proliferation and mediate death of high grade serous ovarian cancer. First is a new class of antibody conjugated drug referred to as Extracellular Drug Conjugate (EDC) which induces apoptosis and autophagy of ovarian cancer cells at low concentration (IC502.5nM). The EDCs are composed of modified cardiac glycoside (CEN-09) conjugated to the antibody through chemical linker. The antibody selectively binds to molecules such as dysadherin that form complex with the Na+/K+-ATPase, and this complex is overexpressed in cancer cells as compared to normal cells. The antibody binding to dysadherin allows the attached drug (CEN-09) to bind to Na/K-ATPase, interfering with the membrane potential and hence causing apoptotic death of cancer cells. The second class of drugs that Yousef investigates are natural compounds. One of these compounds is plumbagin, a small molecule agent extracted from the root of the plant, plumbago. Plumbagin inhibits the proliferation of the cancer cells at an IC50of 3 micromolar. Plumbagin induces cell death through generation of reactive oxygen species (ROS). Generation of ROS after the treatment leading to loss of the mitochondrial membrane potential and induce apoptosis. 1mM of N-Acetyl Cysteine (ROS inhibitor) abrogates the toxicity of plumbagin. Yousef is investigating the effect of plumbagin-induced oxidative stress on Na+/K+ ion transport in cancer cells. Electrophysiology experiments are showing a significant inhibition of Na/K-ATPase due to the action of plumbagin. The physiological significance of this observation is under investigation.

Peter Lewis, PHD

Studies how molecules that “coat” the DNA in our cells can regulate cellular function and influence how cancer cells grow and respond to treatment.

H3F3A (encoding the histone variant H3.3) mutations are likely driver mutations for non-brainstem pediatric high-grade astrocytoma (HGA; G34R/V in 22%-31%). The mechanism of the G34R/V mutations remains poorly understood. In unpublished studies, Dr. Lewis’s laboratory has found that the G34R substitution causes high levels of H3K27me3, a modification linked to gene repression, on the mutant H3.3 protein. His team found that expression of H3.3-G34R exhibit selective loss of H3K27ac, a modification linked to enhancer activity, on a subset of gene enhancers. The coupled loss of H3K27ac and gain of H3K27me3 on H3.3-G34R nucleosomes led to loss of enhancer activity and decreased gene expression. These and other data lead Dr. Lewis to hypothesize that PRC2-mediated gene repression is required for H3.3-G34R­containing HGAs. Dr. Lewis’s research proposes to 1) investigate how genome-wide alterations in histone modifications by H3.3-G34R mutations are reflected at the genome level of polycomb complex distribution and gene expression; and 2) to assess the dependence of polycomb function in H3.3-G34R-containing HGAs using genetic and pharmacologic strategies. To assess the dependence of polycomb function in G34R­containing HGAs, he will use pharmacological and genetic strategies to interfere with the activities of polycomb complexes. Commercially available EZHl/2 inhibitors and siRNAs directed against polycomb subunits will be used for in vitro cell growth assays and in vivo xenograft studies. Additionally, transcriptome and Ch IP sequencing will be employed to monitor changes in gene expression and chromatin modifications upon siRNA or drug treatment. Dr. Lewis expects that loss of polycomb silencing may partially or fully suppress the effects of the G34R mutation.

Mark Klein

Working in the laboratory of Dr. Jon Denu studying how to activate and alter the activity of specific enzymes in cancer cells to improve cancer treatment.

Mark Klein’s work focuses on the tumor suppressor SIRT6, which is an epigenetic enzyme that represses transcription of metabolic and growth genes involved in the Warburg effect of cancer cells. Through small molecule screening efforts, he has identified a number of compounds capable of stimulating SIRT6 activity in vitro. Thus, Mark’s project involves studying SIRT6 at a fundamental level, but also developing small molecule therapeutics to potentially treat cancers in driven by low levels of SIRT6 activity. Candidate compounds have been developed through structure-activity relationship studies and have had their stimulatory effects of SIRT6 well characterized in vitro. Mark’s research will facilitate the cellular testing of these compounds against a number of human cell lines.These studies will evaluate changes in the epigenetic modifications of histone sat known SIRT6 regulated promoters, monitor global changes in histone modifications,and evaluate cellular uptake of small-molecules following treatment.

Mario Otto, MD, PhD

Studies novel and alternative approaches to treat childhood cancer.

NM404, a novel phospholipid ether analog developed at UW, is a promising, tumor-targeting anti-cancer agent that interferes with important signaling pathways in neuroblastoma and other cancers. Radiolabeled derivatives can be used for diagnostic imaging and molecular radiotherapy. Dr. Otto’s lab is investigating promising strategies to integrate NM404 in current pediatric cancer treatment approaches. His preliminary data in a variety of solid tumors are promising, demonstrating anti-cancer effects also in rodent xenograft models, while maintaining a very favorable toxicity profile.