Game-Changer Archives - Page 43 of 44

Tao Lu, Ph.D.

Funded by the Kay Yow Cancer Fund

Ovarian cancer (OC) is the deadliest gynecological cancer. The standard treatment approach for epithelial OC is the combination of a platinum compound, mainly carboplatin and taxane. Although most women initially respond well to treatment, the vast majority experience disease recurrence within 2 years, resulting in a fatal relapse due to chemoresistance. Thus, the development of carboplatin resistance is a major barrier in OC treatment. To date, no effective approaches have been developed to overcome carboplatin resistance. We hypothesize that high expressions of some key proteins lead to carboplatin resistance in OC. Recently, we have developed the innovative validation-based insertional mutagenesis (VBIM) technique for novel gene discovery. In this proposal, our overall objective is to use the VBIM technique, in combination with bioinformatics and other advanced approaches, to identify key proteins that lead to carboplatin resistance in OC cells. Human OC cell lines and OC tumor tissues will be used as our research tools. Overall, our unique and comprehensive approach could yield a set of completely novel carboplatin resistance proteins which might not be discovered using traditional methods. The important findings generated from this work will guide physicians to design more rational and precise therapies with greater effectiveness in a specific OC patient. Moreover, this work could open future opportunities for reversal of carboplatin resistance by developing small molecule inhibitors. Therefore, this work would have a fundamentally transformative effect on OC chemotherapy.

Corinne Linardic, M.D., Ph.D.

Funded by the Apple Gold Group

Rhabdomyosarcoma is a connective tissue cancer with features of skeletal muscle, and the most common soft tissue cancer of childhood and adolescence. While most children with the embryonal variant of rhabdomyosarcoma are cured, there is a sub-group of children with high-risk features, making their chance of survival less than one in three. One hypothesis underlying these high-risk features is that there are rhabdomyosarcoma stem cells that can persist in the body despite current standard therapy. A goal of our research laboratory is to identify the cellular pathways that contribute to this persistence of rhabdomyosarcoma stem cells. Over the past several years we have observed that some cellular pathways active during normal skeletal muscle development have been hijacked by embryonal rhabdomyosarcoma cells. We even think that these development pathways communicate with one another to support and reinforce rhabdomyosarcoma stem cells. Our aim in this project is to understand how these cellular pathways communicate with one another, whether they can be inhibited by gene manipulations or pharmacologic agents, then test combinations of these treatments in rhabdomyosarcoma cells in culture and in laboratory mice. We hope to someday translate these findings to clinical trials, opening the door to new treatments for children with this disease.

Andrew Lane, M.D., Ph.D.

V Scholar Plus Award- extended funding for exceptional V Scholars

Most cancers occur more often in males than in females. We don’t understand why. It isn’t explained by differences in cigarette smoking, for example. Males have two different “sex chromosomes,” called X and Y. Females have two copies of X, but no Y. We think that the X and Y chromosomes influence cancer risk and might explain why some cancers are more frequent in men. We studied cancer cells and were surprised to find that some patients had an excess of mutations in genes that “live” on the X chromosome. 100% of those patients were men. In this study, we will look at mutations on X and Y from thousands of patients with many types of cancer. Differences between men and women could explain some of the disparity in cancer incidence between the sexes. These findings may be relevant in cancers that are more frequent in men, including leukemia, brain tumors, kidney cancer, and bladder cancer. In addition, we will study these genes in the laboratory, comparing male and female cells. We will ask how sex differences in mutations on the X chromosome contribute to cancer. We hope that our research discovers new ways to prevent or treat cancer. Specifically, we want to understand why men and women might have different rates of developing cancer. This work might lead us to consider that men and women with the same type of tumor might best be treated differently.

Randy Kimple, M.D., Ph.D.

V Scholar Plus Award- extended funding for exceptional V Scholars

Our lab is focused on improving treatment for patients with head and neck cancer. This project is studying cells that allow a cancer to spread to other parts of the body (i.e. metastasize). We believe that these same cells, termed cancer initiating cells or CICs, are also resistant to standard treatments. The first two years of V Foundation support has been very helpful. Using cells growing in plastic dishes and mice we have found a key pathway that CICs use to survive anti-cancer treatments. This same pathway also helps these cells to spread to other parts of the body. Our goal for the next year is to study these pathways in human cancers.
We will study whether the genetic information that controls CICs in our models can be used to identify them in human tumors. We want to learn whether tumors with more CICs are more resistant to standard treatments. Finally, we will use tissues from actual patients to study whether patients whose tumors have more CICs are more likely to have aggressive cancers. These experiments will allow us to identify new ways to treat these cancers. We hope to improve our ability to select the right treatment for an individual patient.

Michael Kastan, M.D., Ph.D.

Funded by Genentech and matched funds from the V Foundation

The Duke Cancer Institute and the College of Veterinary Medicine at N.C. State University formed a Comparative Oncology Consortium (COC), taking advantage of their expertise and national leadership in their respective disciplines and their geographic proximity. The goals are to collaborate in pre-clinical and clinical cancer research activities in order to advance our understanding of both cancer causation (a high incidence of specific cancers in specific dog breeds provides opportunities to identify new cancer susceptibility genes and environmental factors in cancer causation) and of behaviors and genetics of specific tumor types, as well as to coordinate clinical trials in humans and canines so that novel therapies can be tested in both settings, with information gained in one setting informing the other. In addition to response outcomes of these cancer therapies, the ability to use biomarkers and pharmacology in the canine models can be a novel addition to the characterization of these new cancer therapies and these insights could result in significant enhancements of clinical trial designs (including dosing, scheduling, and combination therapies) when these treatments are tested in human clinical trials. Cost savings and improved clinical trials design would help encourage pharmaceutical companies to use the canine models as part of the assessment process and would benefit the canine patients by giving them access to these novel therapies.

Wenjun Guo, Ph.D.

V Scholar Plus Award- extended funding for exceptional V Scholars

Cancers are diseases caused by faulty genes. Finding these faulty genes will provide effective targets for treatment. To this end, researchers have discovered many gene mutations in all kinds of cancers. However, cancer cells can acquire random mutations, as they are highly unstable. Thus, it is critical to find out which mutations play a causal role in cancer.

To address this problem, we have developed a novel method for studying cancer mutations. We used stem cells to create breast cancer models carrying patient relevant mutations. Using these models, we will study which mutations are responsible for the resistance to cancer treatment. We focus on the treatment that block an important cancer gene, PI3 Kinase. Faulty activation of this gene has been found in many breast cancers. Thus, it is an important cancer target. We have found a specific gene mutation that causes the resistance to this treatment. In this project, we will understand how does this mutation cause the resistance. Based on our mechanistic finding, we will also develop new strategies to overcome the resistance. Thus, successful outcomes of our study will aid the development of effective cancer therapies.

Steven Grant, M.D.

Funded by Virginia Vine 2016

The promise of cancer therapies that target the mutationally activated “drivers” of malignant behavior is that highly selective drugs can be developed that will be effective with minimal side effects. However, that promise has not been achieved because most cancers rapidly develop resistance to these targeted therapies. Recent experience with the leukemias and lymphomas that respond to the drug ibrutinib provide a sobering example of both the successes and disappointments of these targeted approaches. Whereas many patients with malignancies of B-cells (Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL) or Diffuse Large B-Cell Lymphoma (DLBCL)) show a beneficial response to treatment with ibrutinib, the responses are generally incomplete and often are not durable. The goal of the collaborative research proposal from UVA and VCU is to elucidate the important mechanisms of intrinsic and adaptive resistance to therapies for B-cell malignancies, and use this understanding to develop RATIONAL combinations of drugs that target both the driver of malignancy and the resistance mechanisms. The two groups have over the past few years taken complementary approaches to tackling this problem, and some of these discoveries are now entering clinical trial. The UVA and VCU groups will utilize materials from these clinical trials, as well as preclinical models and patient samples to develop tools to match patients with the most appropriate drug combinations, and to develop additional combinations of targeted therapies that will have deeper and more long-lasting benefits.

Jean Gatewood

Funded by Hooters of America, LLC

In an effort to better understand and meet the needs of women in the Hispanic community, Fox Chase Cancer Center is launching an initiative to learn more about their preferences regarding messages that inform and announce the availability of clinical trials for women with breast cancer.

Fox Chase will host a series of focus groups in order to seek guidance from the community on the impact of current announcements, gauge awareness of the availability of clinical trials options and understand how the messaging can be better enhanced in order to make the value of participation in research studies higher-impact.

We will host two focus groups of 10 women each. Focus group 1 will review the existing, Spanish-written brochure and will complete both pre- and post-user testing. Focus group 2 will review the verbal PSA version of the Spanish-written brochure and will also complete pre- and post-user testing. Using the information and feedback gathered from these focus groups, we will tailor our message moving forward to better increase knowledge about the existence, importance and education regarding the availability of clinical trials to minority women in North Philadelphia.

With a better understanding in place, we hope to see an increase in the number of diverse women joining breast cancer clinical research studies to better reflect the racial and ethnic mix of the clinical patient population.

Robert Gatenby, M.D.

The Robert Shields Memorial Grant for Esophageal Cancer was funded by two fundraisers organized by Frank Cannata: Rolling Thunder’s 2015 “Ride for Freedom,” and The Cannata Report Awards and Charities Dinner

Unlike treatment of other common diseases, cancer therapy is constantly limited by rapid evolution of resistance in the treated (cancer) cells. Unfortunately, the amazing capacity of tumor cells to evolve resistance strategies limits virtually every treatment so that metastatic cancers generally remain fatal.

We propose that, while the ability to evolve confers a great advantage on cancer cells, it also imposes a subtle opportunity for treatment. This is because evolving populations can only adapt to current conditions – they can never anticipate future environments. Importantly we can. In this project we employ a sequence of treatments. The first therapy both actively kills cancer cells and guides the evolution of cancer cells so that development of resistance, although inevitable, uses a cellular strategy that we can attack with the second line therapy. We term this “double bind” cancer treatment strategy. An excellent illustration of this approach is pest management through “predator facilitation.” For example, in the event of a rodent infestation, a farmer may introduce an owl. However, rodents typically adapt to the owl predation by shifting their activity to the safety of shrubs. While this would seem to be discouraging result (similar to evolution of resistance to therapy in cancer), the “resistance” strategy can, in fact, be exploited by the farmer by introducing snakes. This is a double bind because the owls facilitate the hunting success of snakes and vice-versa. In this project we construct a similar evolutionary dynamics for treating esophageal cancer using a combination of target therapy and immunotherapy.

Luigi Franchi, M.D., Ph.D.

Funded by the Dick Vitale Gala in memory of Chad Carr

Approximatively 10 percent of deadly brain tumors in children are diffuse intrinsic pontine gliomas (DIPG), an aggressive cancer that impacts the body’s most vital functions such as breathing and heart rate. DIPG originates from a genetic mutation and creates an environment that hides cancer cells from the immune system, preventing it from recognizing and fighting the disease. While the prognosis for DIPG has not significantly improved in 25 years, immunotherapy — an approach that encourages the immune system to protect against malignant tumors — has yielded remarkable results in patients with otherwise incurable cancers.
Support from the V-Foundation will help U-M scientists as we seek to identify which genetic mutations in DIPG can be targeted in each patient to restore the immune function, either alone or in combination with other immunotherapeutic methods.