Michael Weber, Ph.D.

Funded by the 2015 Virginia Vine

“The Commonwealth Crushes Cancer” event

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.

Steven Grant, M.D.

Funded by the 2015 Virginia Vine

“The Commonwealth Crushes Cancer” event

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.

Hatem Soliman, M.D.

Funded by Hooters of America, LLC

Dr. Hatem Soliman, a researcher and breast cancer medical oncologist at Moffitt Cancer Center, will be conducting a project to help increase accrual to clinical trials for breast cancer patients. The aim of the project is to first assess patient awareness of cancer clinical trials, perceived barriers that may prevent participation and what information would help patients to more readily participate in trials. Information will be collected from a target of 100 Moffitt breast cancer patients. Once this initial assessment is completed, the second aim of the project is to use this information to create a web hosted video to address questions and issues identified through the survey as perceived barriers to breast cancer clinical trial participation and provide vital information that may help increase participation. A short post video survey will be administered to ascertain the impact of the information presented on increasing clinical trial participation. If successful, our ultimate goal would be to expand this methodology to other cancer types to help increase clinical trial participation.

John Cavanagh, Ph.D.

Funded by a challenge grant with

North Carolina State University

The Jimmy-NCSU V Cancer Therapeutic Program allows young researchers the opportunity to work on multiple facets of cancer research in a set of diverse labs, each investigating different approaches for developing cancer therapeutics.

Enhancing cancer drugs
We have discovered molecules that increase the effects of anticancer drugs by several orders of magnitude.  Our goal is to reduce the working concentrations of all anti-cancer drugs in order to mitigate serious side effects.  We will develop and screen our new molecules with both novel and existing chemotherapeutics against a variety of cancer cell lines in order to define the optimum combination treatment.  Initial screens show effects against breast, renal and colon cancer cell lines.

Cell death and tumor formation
The life and death of cells must be balanced.  Normal cells accommodate this balance by invoking programmed cell death pathways, referred to as apoptosis.  In cancer cells, these pathways are defective and normal cell death does not occur, leading to tumor formation.  In addition, faulty apoptosis causes tumor cells to be resistant to chemo/radiation therapies.  If we could make apoptosis occur properly, we slow down tumor formation and overcome this resistance.

The protein caspase-3 controls apoptosis.  If caspase-3 fails to function, cell death does not happen correctly.  We also know that the protein calbindin-D28K binds to caspase-3 and stops it functioning.  If we can stop calbindin-D28K from interfering with caspase-3, apoptosis would occur normally and the risk of cancer developing would be reduced.  Consequently calbindin-D28K is a powerful target for anticancer drug development.

James Ford, M.D.

Funded by the Gastric Cancer Fund

Dr. James M. Ford, M.D., is an Associate Professor of Medicine, Pediatrics and Genetics at Stanford University School of Medicine. He is the Director of the Stanford Cancer Genetics Clinic and the Stanford Clinical Cancer Genomics Program. A recipient of The V Foundation Translational Research grant in 2002, Ford joined the Scientific Advisory Committee in 2003.

Dr. Ford’s research goals are to understand the role of genetic changes in cancer genes in the risk and development of common cancers. He studies the role of the p53 and BRCA1 tumor suppressor genes in DNA repair, and uses techniques for high-throughput genomic analyses of cancer to identify molecular signatures for targeted therapies. Dr. Ford’s clinical interests include the diagnosis and treatment of patients with a hereditary pre-disposition to cancer. He runs the Stanford Cancer Genetics Clinic, that sees patients for genetic counseling and testing of hereditary cancer syndromes, and enters patients on clinical research protocols for prevention and early diagnosis of cancer in high-risk individuals.

Ford graduated Magna Cum Laude with a B.A. degree from Yale University in 1984 and earned his M.D. degree from Yale in 1989. He has been at Stanford ever since, serving as an intern, resident and fellow before earning his postdoc and becoming Assistant Professor in 1998.

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

Funded by the Apple Gold Group

Rhabdomyosarcoma (RMS) is the most common soft tissue cancer of childhood.  Because RMS has features of skeletal muscle, we and others have been trying to understand how muscle development pathways inside the tumor cells have gone awry.  This project will study the role of a protein called SFRP3, which although it takes part in normal muscle formation, is co-opted to support RMS tumor formation.  We aim to understand in more detail how SFRP3 works in RMS, and how to block it.  Our goal is to someday use SFRP3 blockade as a therapeutic intervention.

James Ford, M.D.

Funded in partnership with the Goldberg Family Foundation

We need better tools to screen for and diagnose cancer earlier and at a curable stage in individuals that carry inherited mutations such as BRCA1/2 and other cancer susceptibility genes that put them at high risk for breast, ovarian, prostate, pancreatic and other cancersWe propose to use powerful new approaches for “next-generation” DNA sequencing from standard blood samples to identify circulating tumor DNA mutations as a very sensitive marker of early cancers in high-risk individuals.  These “liquid biopsies may prove to be a far easier and more sensitive way to screen for cancer than our current imaging based approaches using mammograms, MRI’s, etc.  To this end, we have been collecting blood samples from our genetically high-risk patients with and without cancer, and before and after prophylactic or cancer surgeries, for liquid-biopsy analyses using technology developed at Stanford.   

Michael Weber, Ph.D.

The goals of “precision medicine” in cancer are (1) to identify the molecules that drive
the cancer and (2) develop “smart drugs” that block these drivers. These “smart drugs”
should stop the cancer but not be toxic. Many “smart drugs” have been developed, but
the cancer cells adapt and find escape routes. We get many hopeful “responses” to
therapy but disappointingly few “cures.” Our research identifies escape routes that
cancer cells use to evade death, and then uses additional drugs to block the escape
from treatment.

Our approach is already showing success in treating a blood cancer called Mantle Cell
Lymphoma. One of our combinations is causing complete responses in over half the
patients we treat. Unfortunately, many cases show resistance to our drugs, even
though the patients had never previously seen them. We are researching the ways that
cancer cells become resistant to these powerful drug combinations. Our goal is to
achieve deeper responses to therapy and turn the frequent “responses” into genuine
“cures.”

Hatem Soliman, M.D.

Funded by Hooters of America, LLC

Only a small percentage of patients with cancer in the US enroll on to clinical trials. This is creating a bottleneck for the development of new treatments.  Efforts to improve how patients are identified for clinical trials are important to overcome this problem.  One such effort which is showing promise is to use an individual known as a “pre-screener” to aid the clinical team in identifying eligible patients. The pre-screener functions as an extra set of eyes to review information generated from our electronic medical record as their records come in from referring physicians.  They will be trained to look for patients meeting certain eligibility criteria and then notify the clinical team about the matches ahead of their visit. This will allow the team to better prepare and notify the coordinator for the study to be available at that time. The pre-screener will also serve as a resource for patients using our clinical trial education center in the clinic waiting area to help them navigate through the available information to identify a potential trial option to discuss with their physician during their visit.

John Cavanagh, Ph.D.

Recently, researchers in the program have discovered a synthetically accessible class of molecules that appear to increase the effects of novel anticancer drugs by several orders of magnitude.  The overarching goal is to reduce the working concentrations of ALL anti-cancer drugs in order to mitigate serious side effects.  Here, we propose to develop and screen our new molecules with both novel and existing chemotherapeutics against a variety of cancer cell lines in order to define the optimum combination treatment. 
 
Also we are working on tumor formation. 
 
The life and death of cells must be balanced if tissue homeostasis is to be maintained-there should neither be too much growth nor too little death.  Normal cells accommodate this balance by invoking intrinsic programmed cell death, referred to as apoptosis.  Apoptosis is triggered via three signaling pathways.  If apoptosis does not occur correctly and cells do not die, then malignant tumors form.  It is no surprise therefore that countless cancer therapeutics are being developed to control apoptosis. 
 
It is known that all three apoptosis signaling pathways route through a protein known as caspase-3.  If caspase-3 fails to function, then cell death does not happen correctly and cancer occurs.  It is known that a calcium-binding protein known as calbindin-D28K binds to caspase-3 and stops it functioning.  If we can stop calbindin-D28K from interfering with caspase-3, apoptosis would occur normally and the risk of cancer developing would be significantly reduced.  Consequently calbindin-D28K is a particularly powerful target for anticancer drug development. 

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