TX

Recurrent

Read more about Developing EGFRxHER3 bispecific CAR-T cells for targeting EGFR TKI DTPCs

Eliminating Drug-Tolerant Persister Cells Through T-cell Engineering

2023

Partner Awards

Grant title (if any)

EGFR Resisters/LUNGevity Lung Cancer Research Award

Alexandre Reuben, PhD

University of Texas MD Anderson Cancer Center

Houston

In this project, Dr. Reuben and colleagues aim to develop a novel therapeutic strategy harnessing immune response in EGFR-mutant NSCLC. He will use engineered T cells with receptors targeting EGFR antigens to eradicate drug-tolerant persister (DTP) cells, preventing the emergence of resistance following treatment by osimertinib. This work lays the foundation for use of TCR-engineered T cells in treating patients with EGFR mutations.

Research Summary

Although targeted therapies are extremely effective in destroying tumors, they inevitably leave behind a few cancer cells which persist. These are the cells which eventually become resistant to therapy and lead to the death of patients. Although checkpoint blockade immunotherapy has been largely unsuccessful in EGFR-mutant tumors, immunotherapy via cell therapy may offer promise in this setting. EGFR mutations can give rise to short peptides at the surface of tumor cells, called antigens, which allow the immune system to distinguish tumors from their normal counterparts and to specifically destroy them. Importantly, we have identified several antigens that are found solely on or enriched within EGFR-mutant tumors persisting following treatment with EGFR targeted therapies such as osimertinib/Tagrisso. As a result, we have developed a library of receptors which can be engineered into immune cells to allow their direct recognition and destruction of persisting EGFR-mutant cancer cells on the basis of the unique antigens they display. Here, we propose to test a novel approach to eradicate these EGFR-mutant drug persister cells by treating them with engineered immune cells to eliminate the last remaining persister cell and prevent the emergence of resistance following exposure to osimertinib. Our proposal includes two aims: Aim 1 will focus on determining the impact of EGFR-mutant persister cells on the function of immune cells and on their ability to recognize and kill tumor cells. Aim 2 will focus on assessing the ability of receptor- engineered immune cells to eliminate EGFR persister cells when combined with EGFR targeted therapy in vitro and in vivo.
Together, these aims will allow us to determine the therapeutic potential of this novel treatment strategy approach. Our proposal is highly translational, as we have entered into a partnership with Alaunos Therapeutics, a cellular therapy company performing a clinical trial using engineered immune cells at MD Anderson which could facilitate our ability to move these findings into the clinic. Due to the prevalence of the antigens we are targeting (one of which is found in ~90% of lung cancer patients), our approach could extend to almost all patients harboring EGFR mutations.

Technical Abstract

EGFR mutations render lung cancer tumors resistant to immunotherapy via checkpoint blockade. Fortunately, the development of EGFR tyrosine kinase inhibitors (EGFRi) such as Osimertinib has provided impressive clinical responses in a majority of patients. However, many of these patients eventually recur. Studies by our group and others have identified some of the mechanisms associated with resistance to EGFRi. Although EGFRi eliminate the overwhelming proportion of tumor cells, a limited number of cells persist and have thus been termed DTPCs (drug-tolerant persister cells). Importantly, it is these DTPCs which eventually become resistant and are to blame for patient recurrence, highlighting the importance of eradicating these cells before they become fully resistant. Resistance to EGFR TKIs can emerge via two main mechanisms: oncogene-dependent and independent. While oncogene-dependent mechanisms include accumulation of additional mutations in EGFR such as T790M and C797S, oncogene-independent mechanisms include epithelial to mesenchymal transition (EMT) and small cell transformation. Despite their lack of responsiveness to EGFRi at this juncture, each of these mechanisms offers a unique opportunity to leverage cellular immunotherapy to eradicate EGFR mutant DTPCs before they become resistant, thereby improving clinical outcomes. Over the last few years, we have built a library of T cell receptors (TCRs) which confer the ability to recognize epitopes derived from common EGFR mutations including L858R, T790M, and C797S, as well as from the tumor-associated antigen (TAA) FOXM1 which is overexpressed in tumors, and upregulated upon resistance to EGFRi through EMT and small cell transformation. Therefore, we hypothesize that engineering T cells with receptors targeting these EGFR- and FOXM1-derived antigens allows the destruction of DTPCs following treatment with EGFRi, thereby preventing the emergence of resistance. We propose the following specific aims: Aim 1. Assess the impact of drug-tolerant persister cells on CD8 T cell phenotype and function. In this aim, we will identify immune suppressive mechanisms deployed by DTPCs to inhibit T cell response and function. Aim 2. Evaluate the potential of T cell engineering to eliminate DTPCs. In this aim, we will test the ability of TCR-engineered T cells recognizing epitopes derived from EGFR(L858R) and EGFR(T790M) and from the FOXM1 TAA to eradicate DTPCs in vitro and in vivo. Overall, our proposal aims to demonstrate for the first time that TCR engineering can be used in combination with EGFRi to eradicate EGFR-mutant DTPCs. As a result, this work lays the foundation for use of TCR-engineered T cells in this treatment setting. Most importantly, MD Anderson is currently running a clinical trial employing TCR engineering for the treatment of lung cancer with Alaunos Therapeutics which could provide a clear pathway towards the clinic.

Key words

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T cell receptor engineering for the treatment of RET fusion-positive NSCLC

2022

Partner Awards

Grant title (if any)

RETpositive / LUNGevity Foundation Lung Cancer Research Award

Alexandre Reuben, PhD

University of Texas MD Anderson Cancer Center

Houston

Despite advances in the development of RET inhibitors, patients with RET fusions eventually progress. Immunotherapy has been inefficient in patients harboring RET fusions. However, RET fusion proteins themselves may be immunogenic and give rise to an immune response. Dr. Reuben hypothesizes that RET fusions give rise to immunogenic antigens which can be effectively recognized and targeted by engineered T-cells. This project will identify which antigens can elicit an immune response. This information will be used to engineer customized T-cells to gain the ability to recognize those cancer cells that produce these RET fusion proteins. The ultimate goal is to offer new therapeutic alternatives by expanding the possibility of immunotherapy treatment in the overwhelming majority of NSCLC patients harboring RET fusions.

Research Summary

RET fusions are a challenging subset of non-small cell lung cancers (NSCLC). Although initial efforts with multikinase inhibitors resulted in limited success, subsequent development of selective RET inhibitors has bolstered responses for patients harboring these genomic alterations. Despite these advances, patients with RET fusions eventually progress, highlighting the need for additional therapies. Immunotherapy has been inefficient in patients harboring RET fusions. However, RET fusions themselves may be immunogenic. T cells recognize proteins at the surface of cancer cells called antigens, upon which they can specifically destroy tumors. Importantly, fusions constitute a particularly immunogenic antigen type which could be the key to clinical responses. Although T cells harbor millions of different receptors capable of recognizing different antigens, they can be genetically-engineered to recognize an antigen of interest. As such, we hypothesize that RET fusions give rise to immunogenic antigens which can be effectively targeted by engineered T cells. To address our hypothesis, we will identify antigens derived from tumors harboring RET fusions, receptors capable of killing tumors with these antigens and engineer T cells to gain this ability. Our work could be of benefit to patients progressing on selective RET inhibitors. Our goal is to generate a library of TCRs which could be used off-the-shelf to target the two dominant RET fusions (KIF5B-RET=75%; CCDC6-RET=25%) in order to offer new therapeutic alternatives to the overwhelming majority of NSCLC patients harboring RET fusions.

Technical Abstract

Fusions in the RET proto-oncogene account for ~2% of non-small cell lung cancers (NSCLC). Despite initial failures tied to the use of multi-kinase inhibitors, recent selective RET inhibitors have proven remarkably more successful. However, patients eventually recur on these therapies, highlighting the need for other therapeutic alternatives. Immunotherapies have been unsuccessful in patients harboring RET fusions, likely in part due to their low tumor mutational burden. Neoantigens are immunogenic antigens which are derived from somatic mutations, resulting in antigen-specific killing by T lymphocytes. Importantly, insertions, deletions, and gene fusions may exhibit increased immunogenicity, due to their accrued dissimilarity with unmutated transcripts and proteins, which may provide a unique opportunity to target RET fusions using T cell receptor engineering approaches. Accordingly, we hypothesize that RET fusions are immunogenic and can be effectively recognized using T cell receptor engineering approaches. To confirm this hypothesis, we propose to identify RET fusion-derived neoantigens, identify and isolate the T cells which recognize them, and engineer T cells to kill targets in vitro. Through this work, we aim to generate a library of TCRs which could be used off-the-shelf to target the two dominant RET fusions (KIF5B-RET=75%; CCDC6-RET=25%) and 10 most prevalent HLA alleles in the United States, in order to afford new therapeutic alternatives to the overwhelming majority of patients harboring RET fusions in NSCLC.

Key words

RET or rearranged during transfection

Read more about T cell receptor engineering for the treatment of RET fusion-positive NSCLC

Novel structure-based and combinatorial approaches for RET-fusion NSCLC

2022

Partner Awards

Grant title (if any)

The Hamoui Foundation/LUNGevity Lung Cancer Research Award Program

John Heymach, MD, PhD

The University of Texas MD Anderson Cancer Center

Houston

There is an urgent need to identify new agents or combination therapies to benefit patients whose tumors have developed resistance to current RET inhibitors. Currently, the true extent of RET-dependent (resistance mutations in the RET gene) versus RET-independent mechanisms of resistance is unknown. Dr. Heymach’s team will study mechanisms and biomarkers of RET-independent drug resistance and test different drug combinations to overcome RET inhibitor resistance.

Research Summary

RET fusions are oncogenic drivers that are heterogeneous among patients and can occur in approximately 2-3% of lung cancer cases. The treatment of RET fusions has been revolutionized by the development of RET-targeted agents (selperactinib and pralsetinib), but inevitably resistance emerges, and the treatment of resistant disease is a clinical challenge. Resistance is caused by additional mutations in the RET gene (RET-dependent) or changes in other genes/proteins that cause tumor cell growth, but bypass RET inhibition (RET-independent). New studies are urgently needed to identify new agents or combination therapies to benefit these patients. Recently, our team successfully developed a system to classify distinct mutations based on their impact on protein structure and drug sensitivity in EGFR driven lung cancer. We hypothesize that this approach could be used to match patients with RET alterations to the best drugs for each alteration. Building on our previous experience, in this proposal we aim to developing a functional “atlas” of RET fusions and establish a structure/function-based classification approach that would inform clinicians of the best treatment options for RET fusion NSCLC and resistant disease. Further, we will determine mechanisms and biomarkers of RET-independent drug resistance and rational drug combinations to overcome RET inhibitor resistance. These studies will be translated to better guide patient selection and rationale drug combinations for future clinical studies. To this end, we have built a multidisciplinary team with strong expertise in cancer genomics, molecular modeling, and a track record of rapidly translating advances from the laboratory into clinical trials.

Technical Abstract

RET fusions occur in 2-3% cases of lung cancer and there are currently two FDA-approved RET-specific inhibitors, selpercatinib and pralsetinib, for the treatment of patients with RET fusion positive lung or thyroid cancers. Therapeutic resistance eventually emerges, however, and studies have shown that RET-dependent mechanisms of resistance include acquired resistance mutations that alter drug binding. Further, RET fusions and mutations are heterogeneous and the impact of specific fusion partners and RET variants on drug sensitivity is poorly understood. In a recent publication in Nature, our group reported that for a related driver oncogene, EGFR, both primary and acquired resistance mutations can be classified into distinct structural groups that correlate with drug sensitivity and resistance. This structure-function based classification has important advantages 1) structure-based groups predicted drug response significantly better than standard exon-based approaches, 2) this classification enabled us to match drugs for more than ~99% of atypical mutations where currently less than 50% of mutations have an FDA approved drug. In addition, preliminary preclinical and clinical data suggests that two RET-independent mechanisms of resistance- signal bypass and lineage shift-may also drive resistance even in the presence of effective RET inhibition. Applying methodologies we established for elucidating EGFR inhibitor resistance, we will develop a structure-function based classification which can immediately impact clinical decisions for selecting therapies; comprehensively characterize RET-dependent and -independent mechanisms of resistance and biomarkers to assess them; and develop rational therapeutic strategies to overcome resistance which can guide patient selection for future clinical studies.

Key words

RET or rearranged during transfection

Read more about Novel structure-based and combinatorial approaches for RET-fusion NSCLC

SCLC molecular subtypes to predict targeted and immune therapy response

2020

Career Development Award

Carl Gay, MD, PhD

The University of Texas MD Anderson Cancer Center

Houston

Dr. Gay and his team will test an immunotherapy-DNA damage response (DDR) inhibitor combination therapy in SCLC patients and validate a biomarker profile. Dr. Gay’s research aims to develop a new drug therapy combination and determine which patients are likely to benefit from it.

Research Summary

Small cell lung cancer (SCLC) is among the most aggressive malignancies. While this disease responds initially to standard of care therapy, the tumors rapidly develop resistance to these and other available treatments, leading to limited patient survival. Unlike other cancers, where personalized medicine has markedly improved outcomes, small cell lung cancer patients are treated homogeneously, with little understanding of the patients that might best benefit from a specific therapy. Immunotherapy, which has so greatly impacted many other cancers, has shown modest, but promising efficacy for small cell lung cancer patients. We have demonstrated previously that in small cell lung cancer models, immunotherapy response may be enhanced using a class of drugs known as DNA damage repair (DDR) inhibitors. Furthermore, we have developed a potential strategy for optimally identifying patients for DDR inhibitors and immunotherapy using a molecular subtyping approach, which needs validation in patients. We propose using our unique collection of patient-derived mouse models of SCLC, as well as an upcoming trial pairing DDR inhibitors and immunotherapy, to validate our hypothesis. We predict that specific molecular subtypes predict innate sensitivity/resistance and that the ability of SCLC to switch subtypes may underlie acquired resistance. We will examine mouse models and patient samples representing each of the four molecular subtypes and validate predictions for best responses, while performing careful comparisons between samples collected pre- and post-treatment to explore mechanisms of resistance in an attempt to guide future clinical trials aimed at personalization of SCLC therapy.

Technical Abstract

Small cell lung cancer (SCLC) is an aggressive, neuroendocrine malignancy that accounts for approximately 15% of lung cancers. Despite recent advances, including the approval of immunotherapy combined with chemotherapy for frontline treatment, the median overall survival for patients with extensive-stage SCLC remains approximately one year. These dismal outcomes are attributable, in part, to the lack of approved biomarkers for SCLC, which, in turn, is due to the dearth of available tissue for molecular analysis. Using transcriptomic data, we have developed a gene signature that defines four distinct molecular subtypes of SCLC – each with unique biology and therapeutic vulnerabilities. These subtypes are driven by the presence (or absence) of three transcription factors (ASCL1 – SCLC-A; NEUROD1 – SCLC-N; POU2F3 – SCLC-P; and a fourth triple-negative subtype “Inflamed” – SCLC-I) that are largely mutually exclusive. Our preliminary data suggests that inter- and intra-tumoral heterogeneity among these subtypes drives response and resistance to standard and novel therapies for SCLC, including classes such as PARP inhibitors (PARPi) and immunotherapy. We propose applying bulk and single-cell molecular approaches to assign and longitudinally monitor subtype among our established cohort of patient-derived xenograft models treated with PARPi, as well as patient tumor biopsies from an investigator-initiated trial assessing a PARPi/immunotherapy combination. Based on our preliminary data, we hypothesize that SCLC-P and SCLC-I will preferentially benefit from PARP inhibitors and immunotherapy, respectively, and that subtype shifts detectable at the single-cell level along with accompanying shifts in the composition of the immune microenvironment, will govern response and resistance.

Key words

Biomarker or biomarker testing

Circulating tumor DNA

Immune checkpoint inhibitors

Small cell lung cancer (SCLC)

Tumor microenvironment

Read more about SCLC molecular subtypes to predict targeted and immune therapy response

Identification of predictive markers of toxicity to immunotherapy

2017

Career Development Award

This grant was funded in part by the Schmidt Legacy Foundation

Mehmet Altan, MD

The University of Texas MD Anderson Cancer Center

Houston

Side effects associated with immunotherapy (immune-related adverse events or irAEs) with checkpoint inhibitors are different from those seen in other treatment approaches, such as chemotherapy, radiation therapy, and targeted therapies. Their onset is unpredictable, so irAEs require different side-effect management strategies. Dr. Altan is studying how we can predict which patients will develop irAEs so that the best therapy can be selected and symptom management can be proactive.

Research Summary

Identification of key immune escape mechanisms of cancers led to the development of drugs that target these escape mechanisms (immune checkpoints) which have produced durable clinical responses in various malignancies, including lung cancer. Because these drugs (immune checkpoint inhibitors) only benefit a fraction of patients, efforts are now focused on combination treatment strategies to increase responses with the cost of increased toxicities, some of which can be life threatening. Immune checkpoint inhibitors have a unique side effect profile and generally it is due to inflammatory tissue damage, named immune related adverse effects (irAE). Unlike the anticipated side effects of chemotherapies, the onset, duration and severity of side effects of immune checkpoint inhibitors are unpredictable. irAEs share some clinical features with autoimmune conditions. Recent studies suggest 8-9% of the US population carries autoimmune diseases and a quarter of healthy individuals have circulating proteins (auto-reactive antibodies) that are directed against individual's own body. We consider, pre-existing or increasing levels of auto-reactive antibodies and changes in some immune cells caused by immune checkpoint inhibition and radiation therapy, can be predictive markers for toxicity. For this study we plan to use blood samples from patients who are in a clinical trial that combines two immune checkpoint inhibitors with/without radiation therapy. In blood, we plan to measure baseline and subsequent levels of auto-reactive antibodies, and a subgroup of immune cells during therapy. Our goal is to identify a predictive marker set for irAEs and we will also correlate these markers with the response to therapy.

Technical Abstract

Side effects of immune checkpoint therapies, termed immune-related adverse effects (irAEs), are unique and generally secondary to inflammatory tissue damage. The onset and duration of irAEs are unpredictable and predisposing factors for individuals to develop irAEs remains unclear. Some irAEs that emerge with immune checkpoint blockade share clinical features of autoimmune conditions. Preexisting auto-reactive antibodies and their contribution to immune side effects with immunotherapy and radiation have not been defined. This maybe particularly relevant to immune related adverse effects, since recent studies suggest almost 8-9% of the US population carries autoimmune diseases and 26% of healthy individuals have strong IgG humoral responses to variety of self-antigens. For the proposed study, we will use a set of longitudinally collected patient blood samples from a clinical trial which evaluates the clinical activity of combination immune checkpoint inhibitor therapy, nivolumab and ipilimumab with or without local consolidative therapy (stereotactic body irradiation)

We plan to follow preexisting auto-reactive antibodies, baseline T and B cell receptor clonality and their temporal dynamics for combination immune checkpoint therapy with or without radiation therapy and correlate these findings with irAEs and response to therapy.

Key words

Immune checkpoint inhibitors

Liquid biopsy

Radiotherapy

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Axl as a target to reverse EMT, treatment resistance and immunosuppression

2015

Targeted Therapeutics Research Award

Lauren Averett Byers, MD

MD Anderson Cancer Center

Houston

Don Gibbons, Jr., MD, PhD

MD Anderson Cancer Center

Houston

Drs. Byers and Gibbons have discovered that lung cancer cells acquire the ability to hide from the immune system during epithelial-to-mesenchymal transition—a process through which cancer cells develop the ability to spread to other parts of the body (metastasis). The LUNGevity award will help Drs. Byers and Gibbons study the effect of a new drug that can reverse the EMT process and make lung cancer cells more visible to the immune system.

Research Summary

For patients with non-small cell lung cancer (NSCLC), there is an urgent, unmet need for therapies that can overcome resistance to chemotherapy or targeted drugs. Dr. Byers and Dr. Gibbons’ group and others have previously demonstrated that the biological process of “epithelial to mesenchymal transition” (EMT) is a unifying mechanism that drives tumor progression, spread to other parts of the body (metastasis), resistance to standard therapies, and suppression of the anti-tumor immune response. Moreover, they have shown that after EMT occurs: (1) tumor cells overexpress a protein receptor called Axl and immune modulatory proteins (such as PD-L1) that help a cancer cell escape the normal immune system and (2) blocking either Axl or PD-L1 with existing drugs shrinks NSCLC tumors and reduces metastases in mice.

Based on these results, they have developed the first clinical trials of BGB324, an oral drug that inhibits Axl, for lung cancer patients. These will begin patient enrollment this summer. In this project, they will test their hypothesis that Axl drives the EMT process and EMT-mediated immune escape and whether the combination of Axl + PD-L1 inhibitors are more effective than either drug alone (Aim 1); identify biomarkers that predict response to drugs that inhibit Axl (including BGB324) (Aim 2); and test these biomarkers in biopsies from patients treated with BGB324 in the clinical trial (Aim 3).

The ultimate goal of this project is to identify those patients who will benefit the most from drugs that block Axl and to explore whether Axl inhibitors can increase the efficacy of immunotherapy.

Technical Abstract

An estimated 160,000 patients die each year from non-small cell lung cancer (NSCLC), primarily due to the development of metastatic and treatment-refractory disease. Dr. Byers, Dr. Gibbons, and their group have previously demonstrated that the epithelial-mesenchymal transition (EMT) is a unifying mechanism that drives tumor progression, metastasis, resistance to standard therapies, and immune suppression. Furthermore, their group and others have shown that the receptor tyrosine kinase Axl and PD-L1 are overexpressed on tumor cells in the setting of EMT in NSCLC and that targeting either Axl or PD-L1 results in preclinical efficacy in lung cancer models.

Based on these results, they have initiated the first clinical trials of BGB324 (a first-in-class, selective Axl inhibitor) for lung cancer patients in combination with either erlotinib or chemotherapy. They hypothesize that Axl is a driver of EMT and EMT-associated immune escape. Therefore, in this project they will use pre-clinical cell line and animal models to determine the role of Axl in driving EMT, identify predictive markers of response to Axl inhibition, and investigate the efficacy of combination therapy with an Axl inhibitor and an immune checkpoint inhibitor, anti-PD-L1. The biomarkers identified in their preclinical models will be directly tested in fresh tumor biopsies from their Phase 1/2 clinical trial that combines erlotinib with BGB324.

Although NSCLC is a molecularly heterogeneous disease, EMT is a potential universal mechanism of progression and drug resistance across many molecular subtypes. It is their goal to leverage this finding to develop single agent or combination treatment strategies that can be used across the molecular spectrum.

Key words

Biomarker or biomarker testing

Immune checkpoint inhibitors

Read more about Axl as a target to reverse EMT, treatment resistance and immunosuppression

Dissecting novel mechanisms of lung cancer pathogenesis

2015

Career Development Award

Kathryn O’Donnell, PhD

UT Southwestern Medical Center

Dallas

Dr. O’Donnell has discovered that lung cancer cells make a protein called PCDH7 that is present on the surface of cancer cells where it may be accessible to therapies. In cooperation with the KRAS protein, the PCDH7 protein relays signals from outside the cell to make cancer cells grow faster. She is studying the function of the PCDH7 protein and developing strategies to reduce its effect on the KRAS pathway.

Research Summary

Lung cancer is the leading cause of cancer deaths worldwide and is caused by mutations in DNA that promote uncontrolled cell growth or inappropriate cell survival. Dr. O’Donnell and her group have developed a powerful method that creates specific mutations in DNA of human cells growing in the laboratory. Mutagenized cells are assayed for the ability to form colonies in soft agar (a hallmark of cancer cells) or implanted into mice and assayed for their ability to form tumors. After isolating DNA from colonies or tumors, they can identify the genes that have been altered, thus revealing their cancer-promoting properties.

They applied this strategy to human lung epithelial cells with the goal of discovering new driver genes that promote lung cancer. Among the genes they identified in this screen was PROTOCADHERIN 7 (PCDH7), which encodes a poorly characterized cell surface protein. PCDH7 is present at higher levels in lung cancer cells compared with normal lung epithelial cells and high PCDH7 levels correlate with poor survival of lung cancer patients. They demonstrated that elevating or reducing PCDH7 levels in human lung cancer cells strongly potentiates or inhibits their tumor-forming ability, respectively.

The goals of this project are to correlate PCDH7 expression with clinical features in human lung tumors, investigate the mechanisms through which PCDH7 promotes lung cancer development, and begin to develop therapeutic strategies to inhibit PCDH7 in lung cancer patients. These studies will provide a clear experimental foundation for the development of individualized treatment based on targeting PCDH7 or its downstream signaling pathway.

Technical Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the limited effectiveness of current treatments, there is a significant need to identify new driver genes that participate in lung cancer pathogenesis. Dr. O’Donnell and her group identified PROTOCADHERIN 7 (PCDH7) in a functional screen for genes that promote transformation of human bronchial epithelial cells (HBECs). This is of interest because PCDH7 encodes a poorly characterized cell surface receptor that is frequently overexpressed in NSCLC and high expression strongly associates with poor survival of NSCLC patients. Moreover, the presence of PCDH7 on the cell surface highlights the potential of this molecule as a novel target for future therapeutics.

They demonstrated that 1) enforced expression of PCDH7 is sufficient to promote transformation of HBECs, 2) PCDH7 cooperates with oncogenic KRAS to promote tumorigenesis, and 3) PCDH7 potently enhances KRAS-mediated activation of the ERK1/2 pathway. They will elucidate the role of this lung cancer driver by testing the following central hypothesis: Overexpression of PCDH7 initiates a signal transduction cascade that potentiates KRAS-induced MAPK-ERK signaling to promote lung tumorigenesis. In Aim 1, they will correlate PCDH7 immunoexpression with clinical features of resected NSCLCs. In Aim 2, they will elucidate the mechanisms through which PCDH7 potentiates MAPK signaling and tumorigenesis. In Aim 3, they will develop and test the therapeutic efficacy of PCDH7 blocking antibodies in patient-derived xenografts.

These experiments will yield insights into the mechanisms of PCDH7-mediated transformation and reveal new opportunities to pursue this cell-surface receptor as a therapeutic target in NSCLC.

Key words

KRAS

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EGFR/estrogen interactions: role in bronchioalveolar carcinoma and gender differences in the efficacy of antiangiogenic therapy

2007

Targeted Therapeutics Research Award

Funded equally by LUNGevity Foundation and Joan's Legacy

John Heymach, MD, PhD

MD Anderson Cancer Center

Houston

The role of the hormone estrogen in the development of lung cancer has been established. Dr. Heymach is studying how estrogen affects signaling by the EGFR gene and secretion of proteins that fuel the development of new blood vessels necessary to sustain the growth of the cancer.

Key words

Angiogenesis inhibitors

Gender effect

Tyrosine kinase inhibitors (TKIs)

VEGF

Read more about EGFR/estrogen interactions: role in bronchioalveolar carcinoma and gender differences in the efficacy of antiangiogenic therapy

Inflammation-Related Lung Cancer Prevention by Targeting the NF-kB Pathway

2009

Targeted Therapeutics Research Award

American Lung Association/LUNGevity Foundation Discovery Award

Seyed Javad Moghaddam, MD

University of Texas MD Anderson Cancer Center

Houston

Dr. Moghaddam is investigating how airway inflammation can lead to lung cancer. The factor NF-κβ is involved in both inflammation and carcinogenesis. Dr. Moghaddam’s hypothesis is that NF-κβ is a likely candidate for the promotion of lung cancer by inflammation in chronic obstructive pulmonary disease patients.

Key words