Mark Awad, MD, PhD

Funded by Lloyd Family Clinical Scholar Fund

About 5% of non-small cell lung cancers (NSCLCs) have DNA mutations in the anaplasticlymphoma kinase (ALK) gene, and patients with this “ALK-positive” subtype of lung cancer are typically young and have never, or only lightly, smoked. For ALK-positive NSCLC, there are a number of FDA approved oral ALK inhibitor pills, including alectinib, lorlatinib, and brigatinib. While these targeted therapies are initially very effective, the benefit of each of these drugs is usually limited to only a few years because ALK-positive lung cancers almost always develop drug resistance through a variety of complex mechanisms. Although PD-1 inhibitors such as pembrolizumab (Keytruda) have revolutionized the treatment of lung cancer in general, particularly in smoking-associated cancers, most patients with ALK-positive lung cancer do not respond to existing immunotherapies.

We developed an ALK vaccine immunotherapy, composed of small pieces of the ALK protein, which is an effective treatment in animal models of ALK-positive lung cancer. We now plan to launch a first-in-human clinical trial to test this ALK vaccine in patients whose cancer is growing despite treatment with an ALK inhibitor. The vaccine will be tested in combination with an approved ALK inhibitor or with an approved immunotherapy (nivolumab). We will also study immune cells in the blood and in tumor biopsies both before and after vaccination to ensure that this novel therapy is generating a proper anti-ALK immunologic response as we would expect. Our goal is to develop a safe and potent ALK vaccine to improve outcomes for our patients.

Debattama Sen, PhD

Abeloff V Scholar*

CAR-T cells are a new therapy where a patient’s own white blood cells are isolated, modified in a dish to better recognize their tumor, and infused back in. These engineered T cells have transformed the treatment of blood cancers and are being actively considered for solid tumors such as triple-negative breast cancer (TNBC) and ovarian cancer. Unfortunately, CAR-T cell treatment success has been limited partly because these cells eventually lose their ability to control tumors in a process called T cell exhaustion. Understanding why CAR-T cells become exhausted in solid tumors is absolutely required to improve patient outcomes and get better immune-targeted treatment responses. These dysfunctional T cells show many defects, including overproduction of a receptor known as PD-1 that inhibits T cells. It is not currently known why high levels of PD-1 are found on exhausted CAR-T cells and what the consequences of high PD-1 expression are. We hypothesize that by focusing on exhaustion-specific regulation, we can rewire CAR-T cells to prevent PD-1 mediated dysfunction in tumors while minimizing side-effects. These will be attractive targets for translation to early-phase CAR-T clinical trials in breast cancer, ovarian cancer, and other solid tumors, where there is intense interest in reducing T cell exhaustion.

The research project that receives the highest rating by the Scientific Advisory Committee is annually designated as the Abeloff V Scholar. This award is in honor of the late Martin D. Abeloff, MD, a beloved member of the Scientific Advisory Committee.

Francisco Sánchez-Rivera, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund

Humans are genetically diverse and exhibit variable susceptibility to developing diseases with a strong genetic component, leading to significant health disparities. The mechanisms by which certain genetic alterations differentially impact disease development and progression depending on the genetic background and the type of genetic lesion remain poorly understood. To tackle these problems, my group has developed sophisticated methods to rapidly engineer and probe endogenous gene function in primary cells and tissues of living animals in a manner that is agnostic to an individual’s genetic background. My lab is using these methods to elucidate the specific ways that different genetic alterations influence cancer development, progression, and therapy responses, with the goal of using this knowledge to better diagnose and devise novel strategies to target cancers in a more precise, personalized manner.

Miguel Rivera, M.D.

V Scholar Plus Award – extended funding for exceptional V Scholars

Ewing sarcoma is the second most common bone cancer in children and is a very aggressive cancer with a rate of survival of only 60-70%. One important path to finding new treatments for this disease comes from the fact that all Ewing sarcoma cases have an abnormal fusion protein known as EWS-FLI1 which activates genes that drive the formation of tumors. In a prior study we characterized the genes that are activated by EWS-FLI1 in Ewing sarcoma and identified the kinase VRK1 as a promising new therapeutic target. We have also demonstrated that inactivation of VRK1 results in a strong reduction of Ewing sarcoma growth. In this proposal our goal is to characterize the role of VRK1 in Ewing sarcoma and to better understand the mechanisms that regulate its expression in these tumors. These experiments will validate the potential of VRK1 as a therapeutic target and will point to molecular pathways that account for its importance in this disease.

Eliezer Van Allen, M.D.

Funded by the 2016 V Foundation Wine Celebration Fund-A-Need for Prostate Cancer

Nearly all patients with metastatic castration resistant prostate cancer (mCRPC) develop resistance to androgen targeting agents and ultimately succumb to their disease. Recent discoveries by our group and others have demonstrated that a significant proportion of these patients harbor somatic or germline genomic defects in DNA repair defects, and targeting this genomically defined subset with therapies affecting this pathway may impact patient care. The goal of this project is to definitively characterize the genomic and functional landscape of DNA repair defects in mCRPC, clinically test the hypothesis that tumors harboring DNA repair defects preferentially benefit from immune checkpoint blockade, and explore innovative strategies to augment the efficacy of these agents through genomic and preclinical approaches. The project described herein is the first to comprehensively bridge the DNA repair and immuno-oncology fields to directly impact patients with advanced prostate cancer. We propose an integrated strategy that leverages advances in clinical genomics, trial design, and preclinical modeling methodology pioneered by our team. Furthermore, our proposal will be the first to specifically enable immune checkpoint blockade treatment strategies for mCRPC. In summary, this project will catalyze our understanding of how DNA repair defects impact advanced prostate cancer, and how deep knowledge about these events may enable clinical development of a transformative new class of immunotherapies that are greatly needed for advanced prostate cancer patients. 

Nikhil Wagle, M.D.

V Scholar Plus Award – extended funding for exceptional V Scholars

Estrogen receptor positive (ER+) metastatic breast cancer (MBC) remains the most common cause of breast cancer death. Though we have made many advances in the treatment of ER+ MBC, patients invariably develop resistance to therapies. The mechanisms of resistance are not well known. In order to improve survival for patients with ER+ MBC, it is critical to develop an understanding of this resistance.  

We recently found that in 7% of metastatic tumors from patients with resistant ER+ MBC, a gene called the retinoblastoma tumor suppressor (Rb) had been deleted.  Loss of the Rb gene resulted in resistance to multiple agents used for ER+ MBC.  ER+ MBC that lacks Rb likely represents a growing subset of patients in whom standard therapies do not work and in whom we do not know the optimal therapies. Therefore, it is critical to develop novel approaches to treating this subtype of ER+ MBC. 

The goal of this research is to better understand Rb loss in ER+ MBC and identify new therapeutic strategies. To do this, we will utilize cell line models we have generated that approximate ER+ MBC that has lost the Rb gene.  We will characterize these cell lines to identify how they become resistant to therapies, and identify novel therapeutic targets to prevent or overcome this resistance. At the completion of the project, our results should enable the development of clinical biomarkers of response and resistance for patients with ER+ MBC, and, ultimately, the design of clinical trials of therapeutic approaches and rational drug combinations. 

 

Steven Barthel, Ph.D.

V Scholar Plus Award – extended funding for exceptional V Scholars

It is now clear that our immune system has the capacity to both recognize and destroy cancer cells. Unfortunately, tumor cells escape this immune-mediated destruction by activating inhibitory switches to turn off T-cells. These switches, called immune checkpoint receptors (ICR), are now being targeted in early-phase clinical cancer trials in hopes of restoring and boosting immune-targeted killing of cancer.

However, despite showing promise in animal models of cancer, it remains unclear whether drugs targeting more recently identified ICRs will work in humans. Most importantly and a major focus of this proposal, while ICR therapies were previously assumed to bind and target only immune cells as noted above, our data newly identifies ICR expression directly on cancer cells along with therapeutically promising anti-cancer as well as pro-tumorigenic activities. What’s more, levels of cancer cell-ICRs could be dynamically regulated by cytokine stimulation. Overall, these findings raise unanswered questions on ICR-specific drug safety, specificity, potency and optimization that challenge existing, even false, assumptions within the immunotherapy field and invite further inquiry of these entirely unexplored tumor-intrinsic pathways.

This interdisciplinary proposal functionally dissects one particular tumor cell-expressed ICR and its undiscovered roles in cancer progression. As our seminal data reveals that it powerfully regulates cancer growth and metastasis, this research lays the groundwork for developing innovative drugs to block cancer advancement. Results will not only raise awareness of unanticipated impact of ICR drugs on a new tumor-intrinsic pathway but also invite further scientific and therapeutic inquiry and exploitation of this undefined pathway in cancer.

Srinivas Viswanathan, MD, PhD

There are many types of kidney cancer and most current treatments were designed for the commonest type, called “clear-cell kidney cancer.” However, these therapies work less well in other types of kidney cancer. Unfortunately, because the different kinds of kidney cancer can look similar under the microscope, many kidney cancers are misdiagnosed.

One such cancer is “translocation renal cell carcinoma” (tRCC), which makes up about 5% of all kidney cancers in adults and over half of kidney cancers in children. Early and accurate diagnosis of tRCC is important for two reasons. First, this kidney cancer has a poor prognosis and it is vital that patients are accurately informed of their diagnosis. Moreover, an early diagnosis may give a patient the opportunity to cure the cancer through surgery before it spreads. Second, an accurate diagnosis can inform which is the best treatment for a patient to receive.

Although tRCC is frequently misdiagnosed under the microscope, it is unique in terms of the genes it expresses. In this project, we will develop methods to diagnose tRCC based on its distinctive pattern of gene expression. We will apply these methods to both biopsies of tumor tissue and so-called “liquid biopsies,” in which DNA from tumor cells is extracted from a routine blood draw. This work will advance the accuracy and ease with which kidney cancer is diagnosed and may lead to new ways to diagnose tRCC earlier – when it can be caught and cured before it spreads.

Sahar Nissim, M.D., Ph.D.

Pancreatic cancer remains a devastating diagnosis that is incurable in most patients, killing ~50,000 Americans per year. Treatment options including newer immunotherapy approaches are notoriously ineffective. These grim numbers motivate the search for a new strategy called “interception” that might prevent pancreatic cancer altogether. Interception seeks to target the earliest events in the progression of normal pancreas cells into invasive cancer. While this progression spans over a decade, no interception options currently exist.

We have identified a compelling target for interception. This protein is responsible for maintaining the normal identity of pancreas cells, and its activity diminishes as cells progress to cancer. Furthermore, studies comparing thousands of individuals with or without pancreatic cancer have found that this protein impacts risk of developing pancreatic cancer. Lastly, our team has developed potent drugs that can modulate the activity of this protein.

Our goal in this proposal is to pioneer an interception strategy by pharmacologically boosting activity of this protein to prevent progression of normal pancreas cells into cancer. We will characterize the mechanisms and impacts of these new drugs in mouse models of pancreatic cancer as well as in human specimens. Our studies will lay groundwork for clinical trials of interception to prevent pancreatic cancer altogether. Pancreatic cancer interception can also help address issues of psychological trauma associated with diagnosis and unequal access to treatment. Like taking aspirin to prevent heart disease before it happens, we envision these new drugs will be transformative in the fight to end pancreatic cancer.

Lecia Sequist, MD

Lung cancer is the leading cause of cancer death in both the US and the world. There is an effective screening tool called low dose computed tomography (CT) scans of the lungs, which can find lung cancers earlier while curative surgery is still an option. These screening CT scans are recommended once to year for heavy current and former smokers, but only a tiny fraction of those who should be getting lung screening are receiving it, in part because of the high false positive rate with screening CT scans. When lung screening identifies an abnormal area (called a nodule) within the lung, the chances are much greater that it will turn out to be benign rather than cancer. However, to prove the nodule is benign a battery of tests and procedures are often ordered, leading to cost, inconvenience, possible complications, and worry. Our project aims to cut the obstacle of false positive results on lung cancer screening in half by developing a blood test that can be drawn in a doctor’s office after a patient is found to have a lung nodule on a screening CT scan and can help predict whether the nodule is benign or cancerous. The test is built upon a cutting-edge technology called multiplexed mass spectrometry-based plasma proteomics, which can detect the signature spectrum of hundreds of proteins within a patient’s blood plasma using just a small sample. Our test will look at the pattern of proteins to see if the pattern matches those seen in cancer patients. Our long-term goal is to develop an accessible test that will promote increased lung cancer screening uptake and lead to more lives saved.

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