Texas Archives - Page 9 of 9

Benjamin Deneen, Ph.D.

Kenneth D. Westover, M.D., Ph.D.

Funded by The Michael and Carole Marks Family

Multiple lines of evidence suggest that if achievable, inhibiting K-Ras signaling may have therapeutic advantages in cancer. Approximately 30% of all human cancers contain activating Ras mutations making them one of the most common identifiable molecular cancer drivers. Despite almost 30 years of effort, direct inhibitors of Ras family members have failed to achieve success in the clinical setting. Our immediate aim is to develop and evaluate GTP-competitive inhibitors of K-Ras. Our long term goal is to apply this concept to other cancer-related small GTPases and test it as a new therapeutic strategy.

Targeting the GTP binding site of Ras is difficult because it binds to GTP and GDP with high affinity and the intracellular concentrations of GTP and GDP are also high. We recently reported a concept to overcome these obstacles that involves using compounds that form a covalent bond with K-Ras after they enter the GTP binding site. This concept was motivated both by clinically important, time-tested covalent inhibitors like aspirin and penicillin and by recently developed, rationally designed covalent kinase inhibitors such as Ibrutinib and Afatinib which are now FDA approved. Our prototype compound, SML-8-73-1 (SML), is a GDP analogue containing a reactive warhead extending from the beta-phosphate which adds irreversibly to Cysteine 12, a cysteine found in the active site of an oncogenic mutant form of K-Ras that is common in people exposed to cigarette smoke, K-Ras G12C. We have shown that even in the presence of large excesses of GDP and GTP, quantitative complete irreversible binding of SML is observed.

We hypothesize that for non-G12C K-Ras mutants and other cancer-related GTPases the covalent strategy may be applied by targeting a conserved active site lysine. We already know that targeting this lysine with covalent chemistry is possible but we don’t know if this strategy can be adapted to make inhibitors that are selective for particular GTPases and what the impact of these compounds will be on GTPase-mediated signaling. The goal of our work supported by the V Foundation will be to explore this concept by generating and testing new compounds which target the conserved active site lysine.

Keith Syson Chan, Ph.D.

Funded by the Jimmy V Celebrity Golf Classic

Volunteer Award In honor of

Dave Gibson and Felicia Davis

Kenneth Westover, M.D., Ph.D.

V Scholar Plus Award- extended funding for exceptional V Scholars

Cancer is an abnormal state wherein cells become uncontrolled in their ability to divide, grow and cross tissue borders. These cellular processes are governed by an array of signaling proteins including KRAS. Mutations in the KRAS protein result in uncontrolled signaling leading to cancer. KRAS mutations are some of the most common causes of many types of cancer. However, researchers have struggled to discover ways of treating tumors driven by mutant KRAS. The goal of this project is to develop new drugs that directly target mutant KRAS proteins. We will focus on two mutations. One is common in lung cancer, KRAS G12C. The other is common in gastrointestinal cancers, KRAS G13D.

Leonid Metelitsa, M.D., Ph.D.

Funded by the Buster and Kristen Posey Fund

with Recognition to Dick Vitale

In this project, we aim to develop a safe and effective treatment for a childhood cancer called neuroblastoma. Recently, there has been some success harnessing the human immune system to fight cancer. We have developed an immune-based strategy to target one specific cancer-promoting gene that is known to cause an aggressive form of neuroblastoma. This gene is present in about half of all cases with poor disease outcomes in our patient population. We developed a new cancer vaccine for this gene that causes immune cells in the body to fight cancer cells directly. A mouse version of this vaccine proved safe and potent in mice, so we think we can use the same strategy to create a clinical-grade vaccine that will be safe and effective in humans, too. In this study, we first will test each part of this vaccine separately and then will re-assemble them in a very clean laboratory room. Indeed, this vaccine will be produced under such strict conditions that it will be ready for clinical testing in children with neuroblastoma after this grant is completed. Because we are targeting a gene that is expressed on cancer cells but not on cells of healthy tissues, our vaccine is unlikely to be as toxic as others treatments that are available now in the clinic. This vaccine is easy to deliver, as it can be swallowed and so does not involve a shot, making it easier for pediatric patients.

Ann Leen, Ph.D

Our goal is to develop a potent therapy for pancreas cancer – an incurable disease that is resistant to traditional cancer treatments. Challenges involved in treating this disease include: i) a barrier that surrounds the cancer cells (“tumor stroma”) and limits drug access, ii) diversity among cancer cells, making it hard to find a single means of killing all cells, and iii) the harsh cancer milieu, which prevents immune cells from working. Thus, new therapies to beat these barriers are vital and T cell therapy may meet this need. We plan to collect immune cells, called T cells, from patients and in the laboratory we will train them to find and kill tumor cells that display “tumor associated antigens – TAAs” on their surface. We plan to use cells that have been trained to look for tumor cells expressing 5 different TAAs in a clinical trial where we will gauge if this therapy is both safe and active in patients. Next, to ensure that our cells retain their ability to kill in the tumor milieu we will equip them with a special switch that allows them to convert bad signals into ones that are good for our T cells. Hence, we will turn an “off” switch into an “on”. By using this tactic, we hope to boost the activity of our therapy.

Florencia McAllister, M.D.

The most common mutation found in patients with pancreatic cancer is a mutation in the Kras gene. However, this mutation is not sufficient for initiation and progression of pancreatic cancer. It is well known that inflammation is a risk factor for pancreatic cancer and can accelerate pancreatic cancer development. We have shown that during pancreatic inflammation, caused by cigarette smoking, stones, or other stressors, immune cells secreting a factor named IL-17 are recruited to the pancreas and are capable of inducing pancreatic cancer initiation and development. We are now interested in understanding the role of these cells in regulating pancreatic cancer stem cells induction and invasiveness. This information will be useful for pancreatic cancer prevention and treatment given the existence of commercially available monoclonal antibodies that target specifically these cells.

Zhijie (Jason) Liu, Ph.D.

More than 40,000 American women die of breast cancer each year. One out of every eight women in the U.S. will develop invasive breast cancer during their lifetime. In 70% of these women, estrogen and estrogen receptor α (ERα) are key players in breast cancer diseases. Keeping this endocrine signaling function low by endocrine therapy is the best treatment right now. Yet, after 5 years, hormonal treatment stops working in more than 30% of these patients and the disease returns. Because hormone resistance is still a challenge, there are few effective therapies for these patients. We plan to study estrogen and ERα related to hormone resistance.

ERα binds DNA elements that regulate gene expression. These elements are very important in cancer development and progression. When these elements lose control, breast cancer becomes resistant to hormones. Thus, if we can find ways to understand and correct these elements in hormone resistant cells, we can find cures for ERα-positive breast cancers. The goal of this project is to understand how ERα controls DNA elements. We will identify markers to measure the presence and progression of breast cancer. Our research results may lead to new therapies that target this disease. Discoveries from this project may help with treating other cancers and may be useful for other research fields.