Current Grants

Each year, LCRF selects a group of grant recipients that demonstrate promise and ingenuity in their work. After receiving seed funding from LCRF, these researchers are often better prepared to demonstrate proof of concept and secure additional funding from governmental and other sources.

Learn more about current grant recipients below.

2016 Lung Cancer Research Foundation Annual Grant Recipients

Yale University

Principal Investigator:

Nadya Dimitrova, PhD

Research Project:

Making first strides towards elucidating the importance of long noncoding RNAs in lung cancer

Summary:

Over the past decades, the search for drivers and therapeutic targets in cancer has primarily focused on protein-coding genes, which account for less than 2% of the human genome. Recent technological advances in deep sequencing have revealed that over 70% of mammalian genomes is actively transcribed into thousands of long transcripts that do not encode for proteins. Until recently regarded as “junk DNA”, there is a growing recognition that this new class of genes, called long noncoding RNAs, regulates a wide range of biological processes. The importance of long noncoding RNAs in influencing disease states, such as cancer, however, remains vastly understudied.

With the generous support from the Lung Cancer Research Foundation, the Dimitrova lab will develop and utilize innovative approaches to shed light on the contribution of long noncoding RNAs to lung cancer development. The aim is to elucidate how altered expression of long noncoding RNAs promotes or suppresses tumor growth and to identify the key elements that underlie their roles in cancer. With the advent of technologies that can interfere with RNA function, these studies will lay the foundation for the development of tools that harness the power of long noncoding RNAs for therapeutic applications.

The University of Texas MD Anderson Cancer Center

Principal Investigator:

Yasir Elamin, MD

Research Project:

Identification and targeting primary resistance mechanisms in lung cancer patients with EGFR mutations

Summary:

Mutations in the EGFR gene can drive lung cancer cells growth, survival and spread. Patients whose tumors contain these mutations can benefit substantially from targeted therapy with an EGFR inhibitor. Unfortunately, a subset of these patients do not respond to EGFR inhibitors. Dr Elamin's study will focus on this group of lung cancer patients with primary resistance to currently available EGFR inhibitors. Specifically, he will study a novel EGFR inhibitor with promising activity in lung cancer patients. Working with a group of clinicians and scientists, they will analyze DNA, RNA and protein obtained from patients treated within a clinical study of this novel EGFR inhibitor. The team will then determine the mechanisms by which lung cancer cells evade treatment. They will also study potential resistance mechanisms and treatment strategies that may overcome resistance in mouse models. The overall goal of this study is provide EGFR mutant lung cancer patients with a new effective treatment option.

Georgetown University

Principal Investigator:

Giuseppe Giaccone, MD, PhD

Research Project:

Resistance to targeted therapy in lung cancer

Summary:

Patients with lung cancer may have genetic alterations (mutations) in the epidermal growth factor receptor (EGFR) gene. These mutations are much more common in never-smoker patients, women, Asians and patients with lung adenocarcinoma subtype. The presence of these mutations renders the tumor sensitive to EGFR inhibitors, which are now the preferred treatment of patients with advanced EGFR-mutated adenocarcinoma of the lung instead of chemotherapy. Although EGFR inhibitors are able to shrink the tumors in the majority of patients, a significant number of patients do not have a major benefit from these treatments and all patients develop resistance after an initial benefit. We have identified a protein, called Cripto-1, that when it is at high level in lung cancer cells, determines insensitivity of the tumor to EGFR inhibitors (intrinsic resistance). The Cripto-1 protein, besides being present on the membrane of the tumor cells, is also released by the tumor cells into the blood circulation. We have preliminary evidence that Cripto-1 protein can cause cancer cell resistance to EGFR inhibitors when it is present at high levels in several EGFR-mutated cancer cell lines. In this project we will investigate whether different Cripto-1 forms, that have been genetically engineered to be secreted or not from cancer cells, will be able to cause resistance to EGFR inhibitors in lung cancer cell lines and in animal experiments. We will also study Cripto-1 levels in plasma of patients with EGFR mutant lung adenocarcinoma, treated with EGFR inhibitors, to see whether the presence of Cripto-1 in the blood correlates with the level of Cripto-1 in the tumor. We will also investigate in this group of patients whether the levels of Cripto-1 in plasma is correlated with response to the EGFR inhibitors. If this is the case, Cripto-1 levels could in the future be used to stratify patients with EGFR mutant lung adenocarcinoma for EGFR inhibitor treatment.

Memorial Sloan Kettering Cancer Center

Principal Investigator:

Benjamin Lok, MD

Research Project:

Understanding small cell lung cancer drug sensitivity to a targeted drug (PARP inhibitors) and therapeutic radiation by genetic screens

Summary:

A new targeted therapy for small cell lung cancer (SCLC) known as PARP inhibitors excitingly has provided a potential new treatment option for SCLC patients. Understanding who would or would not respond to this new therapy would be important to maximize the potential benefit to patients. We will tackle this problem with genetic screens using new technology know as CRISPR-Cas9 that allows for precise modification of all genes in a cancer cell line. We will use this technology to identify which genes lead to response or resistance to PARP inhibitor therapy that in turn may lead to other new approaches to increase our ability to treat our patients. In addition, therapeutic radiation is used in many SCLC patients and benefits many patients. Understanding what genes influence response to radiation would be important through this same genetic screening technology. We hope to use findings from this project to improve our ability to treat and cure more patients afflicted by this disease.

Weill Cornell Medical College

Principal Investigator:

Rossella Marullo, MD, PhD

Research Project:

Elucidating the biological functions of a novel therapeutic target in non-small cell lung cancer

Summary:

Novel therapeutic strategies are urgently needed for non-small cell lung cancer, as the prognosis of patients with advanced stages remains dismal. Dr. Marullo’s research has revealed that a subgroup of non-small cell lung cancer relies on the activity of a protein called BCL6 to survive. By repressing multiple genes, BCL6 promotes tolerance to oncogenic-associated stresses, among which stress derived from genomic damage, thus resulting in resistance towards the chemotherapeutic drugs currently in use to treat lung cancer patients. Better understanding of the role of BCL6 in lung cancer is particularly relevant as small molecule inhibitors of BCL6 are currently under development. By characterizing the molecular programs regulated by BCL6 in lung cancer, Dr. Marullo aims to elucidate the molecular mechanisms through which BCL6 promotes survival and chemoresistance in this disease. This knowledge will be then applied to optimize the use of BCL6 inhibitors, alone or in combination with chemotherapy, for the treatment of non-small cell lung cancer.

Stanford University

Principal Investigator:

Hiromitsu Nakauchi, MD, PhD

Research Project:

Exploring novel rejuvenated T cell immunotherapy for lung cancer

Summary:

Lung cancer remains the leading cause of cancer death worldwide. Mutations that activate epidermal growth factor receptor (EGFR) account for most of mutations in advanced lung cancer. Tyrosine kinase inhibitors (TKIs), showed therapeutic efficacy when such EGFR mutations are present. However, patients frequently develop resistance to TKIs with secondary mutations. Among them, a new point mutation called C797S occurred after 3rd generation TKI (AZD9291) treatment and is the major mechanism that causes cancer relapse and death. Currently, there is no treatment for patients with this type of EGFR mutation. In this project, we will generate killer T cells from relapsed patients specific to this mutation and apply them for T-cell immunotherapy. Furthermore, using the most state-of-art induced-pluripotent stem (iPS) cell technology, we will try to rejuvenate such killer T cells for higher killing activity and to provide unlimited supply for treatment. We will perform this proof-of-concept study in collaboration with Stanford oncologists.

Dana-Farber Cancer Institute

Principal Investigator:

Matthew Oser, MD, PhD

Research Project:

Identification of new therapeutic targets for small cell lung cancer

Summary:

Small cell lung cancer (SCLC) accounts for 10-15% of lung cancer with 30,000 new patients diagnosed in the United States each year. In contrast to non-small cell lung cancer (NSCLC), DNA sequencing studies have not identified frequently mutated oncogenes in SCLC and there are no targeted therapies for SCLC. SCLC is universally characterized by mutations or loss of the RB1 tumor suppressor gene. Dr. Oser uses CRISPR to perform genetic screens to identify new therapeutic targets in SCLC whose effects require the loss of RB1. This concept, known as synthetic lethality, offers the exciting prospect of identifying highly specific targeted therapies with minimal side effects. In addition, Dr. Oser uses CRISPR to develop new mouse models of SCLC to efficiently and rapidly test novel therapeutic targets.

The University of Texas MD Anderson Cancer Center

Principal Investigator:

Edwin Ostrin, MD, PhD

Research Project:

The immunoproteasome -- investigating a new interaction between lung cancer and the immune system

Summary:

As lung cancer develops, it has to escape detection and elimination by the immune system. New drugs that reverse this, and allow the immune system to better attack a growing cancer, are under intense investigation. Early data shows that such treatment, termed immunotherapy, is very effective in many lung cancers.

The immunoproteasome is a cellular machine that degrades proteins into short peptide strings that a cell uses to produce a damage signal for the immune system. These damage signals are recognized by a class of immune cells that then can kill the cell with the peptide string on its surface. Lung cancer can stimulate inflammation, and early lung cancer cells use the immunoproteasome to signal to the immune system. Some lung cancers that display markers of a more aggressive behavior turn off their immunoproteasomes, display less of this damage signal, and thus evade the immune system. This proposal seeks to study the exact role of the immunoproteasome in lung cancer development and progression using animal and cell models. This work will test if treatments that turn back on the immunoproteasome in such cancers are a useful strategy that may work in concert with immunotherapy.

University of North Carolina

Principal Investigator:

Chad Pecot, MD

Research Project:

Targeting the immune system to block the spread of lung squamous cancers

Summary:

While targeted therapies of lung adenocarcinoma have improved patient survival, similar advances in lung squamous carcinoma (LUSC) have been stagnant. Recent analyses of the genes that characterize LUSC have revealed they are highly idiosyncratic tumors with no clear “smoking gun” drug target. Recently, however, the use of new therapies that activate the immune system has demonstrated remarkable promise in LUSC.

We have uncovered a previously unrecognized group of LUSC patients whose tumors manipulate the immune system for its own advantage. Remarkably, this group accounts for nearly half of all LUSC patients. Through extensive analysis of the Cancer Genome Atlas (TCGA), as well as through novel cancer models we have developed, we found that LUSC metastasis are driven by immune cells called monocytes.

Here, we hypothesize that (i) blocking monocytes in LUSC will stop its spread and will be synergistic with already proven immune therapies, (ii) a gene signature we have developed will determine who will benefit from immune therapies, and (iii) that proteins in LUSC tumors will establish a biomarker of patients likely to respond to drugs blocking monocytes. The objectives of this proposal are 1) to determine the therapeutic role of targeting monocytes in LUSC, alone or in combination with a proven immune therapy, and 2) to develop predictive biomarkers of response to these novel immune therapies, which will be useful for design of an already planned Phase II clinical trial.

City of Hope Cancer Center

Principal Investigator:

Dan Raz, MD, MAS

Research Project:

Incorporating lung cancer screening education into tobacco cessation counseling

Summary:

Lung cancer screening (LCS) with low dose radiation computed tomography (LDCT) substantially reduces lung cancer mortality and is recommended by the US Preventive Services Task Force (USPSTF) and many other medical organizations. Despite this, few eligible patients are being screened for lung cancer. Although the number of patients screened for lung cancer is low, hundreds of thousands of smokers seek tobacco cessation services nationwide annually. Tobacco cessation counseling may be an important opportunity to educate and counsel eligible patients on LCS with LDCT. We seek to understand the perceptions of lung cancer screening among patients in a large regional tobacco cessation program, and to study the effect of LCS education on tobacco cessation rates and LDCT utilization in a tobacco cessation group-class setting. To accomplish these objectives, we will first administer a brief survey on lung cancer risk perception, knowledge of lung cancer screening, and barriers to LCS in patients who meet eligibility criteria for LCS who have recently enrolled in tobacco cessation counseling in Southern California Kaiser Permanente. Next, we will incorporate LCS information into tobacco cessation group-classes in selected Southern California Kaiser Permanente sites and study the effects of this educational intervention on tobacco cessation and utilization of LDCT for LCS at 6 months. These data are important so that we can determine if education on LCS during tobacco cessation impacts tobacco cessation and whether there is an effect on LCS utilization.

University of Texas at El Paso

Principal Investigator:

Rachid Skouta, PhD

Research Project:

Identification of promising novel drug candidates for non-small cell lung cancer

Summary:

Lung cancer is the leading cause of cancer death among both men and women in the United States. Non-small cell lung cancer (NSCLC) represents more than 85% of lung cancer cases. The predicted 5 year survival rate of the NSCLC case is around 16% due to a lack of understanding of the dynamic interactions between the tumor microenvironment and drug resistance. Therefore, there is still a need to discover anti-NSCLC drug candidates acting through new complementary mechanisms of cell death and therapeutic targets. Such candidates targeting new proteins may have efficacy against difficult-to-treat NSCLC. The proposed studies are designed to discover novel specific ferroptosis inducers of well-defined cell death and uncover their target for disease treatments. In addition, these studies will improve possible resistance that increases towards agents activating a known apoptosis cell death. Thus, completion of these studies may provide knowledge that can be used to increase drug efficiency against NSCLC.

Fred Hutchinson Cancer Research Center

Principal Investigator:

Joshua Veatch, MD, PhD

Research Project:

A new vaccine approach to induce T cell immune responses in lung cancer

Summary:

New drugs that enhance the function anti-tumor immune cells (T cells) have shown promise in treating lung cancer, but unfortunately most patients still do not respond to these drugs. A key reason these drugs fail is not enough of a T cell immune response against the cancer. While vaccines work well at preventing infectious disease, getting good T cell responses to tumors has been a challenge. This project seeks to develop a new vaccine approach that will induce better T cell responses against lung cancer.

It turns out that T cells themselves, when removed and modified to carry an antigen target, and given back to a patient, are good at inducing new T cells to attack that antigen. This project will develop an approach using T cells carrying cancer antigens (vaccine cells) to induce anti-cancer T cells to fight tumors in mouse models of lung cancer. As the best immune responses occur when antigen is combined with immune danger signals, this project will also test whether the addition of danger signals to the vaccine cells can lead to a better immune response and anti-cancer effect. The goal is to translate this approach to patients for the treatment of lung cancer.

The University of Chicago

Principal Investigator:

Ralph Weichselbaum, MD

Research Project:

Overcoming treatment resistance in lung cancer

Summary:

Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death in the United States. Approximately 221,000 new diagnoses and over 158,000 deaths from lung cancer occur annually. Radiotherapy is a key component of lung cancer treatment, often in combination with surgery and chemotherapy. Unfortunately, treatment failure occurs in up to 60% of localized lung cancers and contributes significantly to patient death. Treatment failure is caused in part by the tumor’s ability to resist both radiotherapy and chemotherapy. Methods to increase tumor sensitivity to both radiotherapy and chemotherapy are critical to improve treatment effectiveness and patient survival.

Recently, a group of researchers led by Dr. Ralph Weichselbaum identified a new, previously unrecognized mode of radiotherapy and chemotherapy action on tumor cells through the production of interferons, which are signaling proteins that help to activate the body’s own defense system (its immune system) against pathogens, like cancer cells and viruses. Their proposal seeks to unravel the mechanisms involved in activating or inhibiting the production of interferons in order to develop therapies that increase activation and/or decrease inhibition of interferon production. They will also test several drugs for their ability to enhance existing lung cancer therapies.

University of Massachusetts Medical School

Principal Investigator:

Wen Xue, PhD

Research Project:

Treating KRAS-mutant lung cancer by inhibiting the NF-kB pathway

Summary:

More than 30% of NSCLC patients carry mutations in the KRAS oncogene. Yet, there are no effective KRAS inhibitors in the clinic. Dr. Xue and his team aim to investigate inhibitors of the NF-kB pathway as a new targeted therapy for KRAS-mutant lung cancer. First, they will identify mechanisms of drug resistance to NF-κB inhibitors using genetic screens. Second, they will determine the therapeutic efficacy of a combination of NF-κB and MEK inhibitors in a mouse model of lung cancer. These studies will allow the team to devise a new approach in exploring NF-κB as an Achilles’ heel in KRAS-mutant lung cancer, and develop combinatorial treatment for these patients.

Emory University

Principal Investigator:

David Yu, MD, PhD

Research Project:

Targeting EZH2 for small cell lung cancer therapy

Summary:

Small cell lung cancer (SCLC) is the most lethal type of lung cancer with a median survival of less than 24 months for all patients. Most current therapies, including the first-line chemotherapeutic regimen of cisplatin and etoposide, rely on inducing DNA damage and blocking DNA replication to cause cell death; however, the effectiveness of these treatments is often limited. While most patients will initially respond to treatment, most will ultimately fail because the cancer develops treatment resistance. Thus, more effective treatments are urgently needed. Recent data in the lab suggests that EZH2 is a critical determinant of cisplatin resistance in SCLC. Importantly, EZH2 is overexpressed in SCLC and implicated in its progression. The hypothesis that will be tested is that EZH2 plays a critical role in mediating cisplatin resistance in SCLC by promoting DNA damage response activities, and furthermore that EZH2 inhibition will sensitize cisplatin-resistant SCLC cells and tumors to cisplatin treatment. We propose to determine how EZH2 mediates cisplatin resistance in SCLC and if EZH2 inhibition can be an effective therapeutic strategy. Completion of this work will define a novel role for EZH2 in the DNA damage response in mediating cisplatin resistance in SCLC and elucidate the significance of EZH2 as a novel therapeutic target for improving the efficacy of treatment for patients with SCLC who develop treatment resistance. We anticipate that following completion of this work, a randomized clinical trial investigating the use of EZH2 inhibitors for patients who have relapsed on cisplatin-based chemotherapy will be initiated, which will help bring to fruition the use of EZH2 inhibitors as a paradigm-changing approach for patients with cisplatin-resistant SCLC in the next few years.