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Synergistic expression of combined RT and dual-immune checkpoint blockade

2022

Health Equity and Inclusiveness Research Fellow Award

Rebecca Shulman, MD

The Research Institute of Fox Chase Cancer Center

Philadelphia

Recent studies have shown that high and low dose radiation used in combination with immunotherapy have a synergistic effect in modulating the growth of satellite tumors, which are tumor cells located near the primary tumor. In this study, Dr. Shulman proposes using an animal model of metastatic lung cancer to test the hypothesis that radiation given in repeated very low dose pulses in combination with immunotherapy can further enhance immunotherapeutic benefit in metastatic lung cancer.

Research Summary

Radiation therapy has become a staple of cancer treatment because it provides a method for producing lethal damage in cancer cells while sparing nearby healthy tissues. Only more recently has it been shown that radiation may also control the growth of satellite tumors–tumors far from the radiation target. This capacity of radiation to affect tumors indirectly is called the abscopal effect and appears to occur because radiation of a small target area stimulates an immune system response throughout the entire body. The demonstration that radiation therapy can augment the body’s natural immune defenses in this way, producing regression of non-irradiated tumors, has led to a radical rethinking of the therapeutic uses of radiation. Thus, contemporary treatment strategies in radiation oncology are based not only on the capacity of radiation to kill cells directly but rely also on remote immune-mediated effects to destroy cancers that have spread. One of the most promising of such strategies involves a combination of radiation therapy and drugs that stimulate the immune system (immunotherapy). In our laboratory, we have tested such a regimen in a mouse model of disseminated lung cancer and have shown that high-dose radiation therapy delivered to select tumors in combination with two immunotherapy agents can significantly inhibit the growth of satellite tumors. We would now like to extend our results with immunotherapy and high-dose radiation by developing a protocol that further exploits the ability of radiation to work in synergy with our natural immune responses. Several research groups have reported favorable results combining immunotherapy both with high-dose radiation and with low-dose radiation delivered to other secondary tumors. Preliminary evidence, however, suggests that low-dose radiation may actually do more to enhance natural immune defenses if it is given in the form of repeated very low dose pulses. The present study will thus employ an animal model of disseminated lung cancer to test a new radiation protocol with possibly enhanced immune effects. The results will determine if the therapeutic efficacy of immunotherapy in combination with high-dose and low-dose radiation can be improved by the use of low-dose radiation given to satellite tumors in the form of repeated very low-dose pulses.

Technical Abstract

Our laboratory has demonstrated the potency of the abscopal effect in studies showing that high-dose radiation therapy delivered to primary tumors in combination with dual immune checkpoint blockade can significantly inhibit the growth of satellite tumors. The implication of such results is that radiation therapy has remote effects which are immune-mediated and that new radiation protocols can be devised to exploit our naturally occurring defenses against cancer. Previous studies have shown that immune-mediated tumoricidal effects can be augmented by combining high-dose radiation therapy delivered to a primary tumor site with low-dose radiotherapy (LDRT) targeting secondary tumors. Tumor response is further enhanced if systemic agents are employed to induce immune-checkpoint blockade (ICB). Such protocols employing conventional LDRT are known to reduce the number of regulatory T cells (Tregs) and to activate natural killer cells, thereby modulating the tumor microenvironment (TME). Our laboratory project seeks to test a modification of LDRT called pulsed low-dose-rate radiotherapy (PLDR). By providing radiation in repeated very low doses, the PLDR regimen may reduce the encasement of tumors with stromal elements, thus removing a barrier to infiltrating immune-reactive cells. We propose to use the immunocompetent lung cancer murine model which we developed for our earlier research combining HDRT with anti-PD1 and anti-CTLA-4 antibodies. HDRT will again be delivered to primary tumors in combination with dual ICB. Additionally, LDRT will be delivered to secondary tumors, both in conventional form and as PLDR. The results will thus test an innovative method for exploiting the emerging synergies of radiation and ICB. A demonstration of the superior therapeutic utility of PLDR in our animal model would be of immediate relevance to clinical trials seeking improved strategies for treating patients with metastatic lung cancer.

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Disparities in NSCLC molecular testing

2021

Health Equity and Inclusiveness Junior Investigator Award

Melina Marmarelis, MD

The University of Pennsylvania

Philadelphia

Research Summary

Detection of genetic changes in lung tumors has improved our understanding of what drives lung cancer to grow. Importantly, highly effective anti-cancer pills have been developed to target tumor genetic changes in genes such as EGFR, ALK or ROS1. Patients with targetable genetic changes live longer if they are able to receive a targeted pill-based therapy compared to conventional lung cancer treatments. It is therefore imperative that we find these targetable genetic changes when they exist.

Previous studies have shown that targetable genetic changes in lung tumors are more common in women, never smokers, younger adults, and people of Asian descent. Because of this association, patients without these characteristics do not always have their tumor tested to find these genetic changes. This project will look at over 2000 patients with targetable genetic changes in EGFR, ALK or ROS1 and investigate whether patient characteristics not usually associated with detection of a targetable genetic change (e.g. male gender, age >65, smoking history, African American, Hispanic) are associated with delayed detection of a target and delayed receipt of the targeted therapy. In addition, we will look at the effect of delayed receipt of targeted therapy on survival and frequency of cancer spreading to the brain. We hypothesize that delayed receipt of targeted therapy could lead to shorter survival and a higher incidence of spread to the brain. These findings will help us develop interventions to improve detection of these targets and delivery of targeted therapy for all lung cancer patients.

Technical Abstract

Background: Patients with NSCLC whose tumors harbor a targetable molecular alteration have improved outcomes when they receive targeted therapy. Historically, targetable alterations have been associated with specific patient characteristics such as female gender, young age, non-smokers, and Asians. Given this association, patients with characteristics not commonly associated with targetable mutations do not always receive timely and complete molecular testing. We hypothesize that male gender, age >65, history of smoking, African American race and Hispanic ethnicity will be independently associated with delayed detection and treatment of a targetable alteration. We will evaluate the impact of delayed targeted therapy on overall survival and brain metastasis development.

Methods: We will perform a retrospective cohort study of approximately 2200 patients with EGFR, ALK or ROS1 targetable alterations obtained through multi-institution retrospective chart review. Multivariate logistic regression will be used to evaluate the association of patient characteristics with complete molecular testing prior to first-line therapy, targeted therapy as first-line therapy, and development of brain metastases. Kaplan-Meier methodology will be used to estimate median overall survival. The log rank test will be used to compare median overall survivals. Multivariate Cox Regression will further evaluate interactions between delayed targeted therapy and patient characteristics as well as help control for potential confounders.

Importance: This will be the first study to evaluate the impact of delayed detection and delayed treatment of driver mutations in NSCLC. This information is critical to designing interventions to improve outcomes in patient groups with characteristics not usually associated with driver mutations.

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Optimizing biomarker based strategies for lung cancer screening

2021

Early Detection Award

Anil Vachani, MD

University of Pennsylvania

Philadelphia

Currently, low-dose computed tomography (LDCT) is the only tool for the screening and early detection of lung cancer in individuals who meet screening criteria. LDCT is not very sensitive; often, abnormalities identified in an LDCT scan turn out to be benign. However, ruling out cancer requires an invasive biopsy. Dr. Vachani is testing whether a biomarker signature can be integrated into LDCT screening to improve the sensitivity of LDCT so that patients may be spared unnecessary biopsies.

Research Summary

Lung cancer remains the leading cause of cancer-related mortality in the US and globally accounting for 1.8 million deaths annually. Use of low-dose CT (LDCT) for lung cancer screening has been shown to save lives and is recommended for individuals at high-risk of lung cancer. However, LDCT has potential risks including a high rate of false positive findings, which may result in additional testing and potentially harmful invasive procedures. Several blood and imaging biomarkers have emerged as potentially useful complementary tools for lung cancer screening (LCS). Our proposed research will use a computational framework to estimate the population level impact of biomarker-based tests and identify the optimal strategy for integration of these emerging tools into LCS and pulmonary nodule evaluation.

Technical Abstract

Lung cancer remains the leading cause of cancer related mortality in the US and globally— responsible for ~1.8 million deaths annually. Randomized trials of low dose CT (LDCT) for lung cancer screening have demonstrated a clear mortality benefit and are recommended by the United States Preventive Services Task Force (USPSTF). However, most individuals currently eligible for screening do not have lung cancer and many at risk populations are not candidates for screening. Additionally, LDCT has a relatively high rate of false positives leading to potentially harmful tests and invasive procedures. Moreover, early experience suggests that LCS outcomes in clinical practice may differ from those observed in randomized trials. Given the concerns with the performance of LDCT, the use of blood and imaging biomarkers to complement the screening process has the potential to enhance its efficacy and effectiveness. Biomarkers could be employed at two different steps of the screening process – as the initial test for cancer screening, to better define the best candidates for screening, or following a positive LDCT scan, to inform lung nodule evaluation and management. While several screening and diagnostic biomarkers have been developed, they have not been formally evaluated in prospective comparative effectiveness trials, nor have they been subjected to cost-effectiveness analyses. More importantly, their impact on lung cancer burden at the population level is still unknown. Our proposed research will inform the following areas of LCS and biomarker discovery: 1) generate a computational framework to estimate and compare the population impact of emerging screening and diagnostic biomarkers, 2) identify the optimal strategy of integrating biomarker tests into LCS, and 3) highlight and identify the characteristics of biomarkers (sensitivity and specificity for histological subtypes, etc.) which are critical for cost-effective biomarker applications.

Key words

Early detection

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Phase II study of pembrolizumab and itacitinib (INCB39110) in NSCLC

2019

Career Development Award

Joshua Bauml, MD

Perelman School of Medicine—University of Pennsylvania, Abramson Cancer Center

Philadelphia

The lung cancer treatment landscape is rapidly evolving with the advent of immunotherapy. Now, three checkpoint inhibitors are available in the first-line and second-line settings for certain subsets of patients with advanced-stage NSCLC. Despite this promise, a large subset of patients treated with immunotherapy will not respond to these drugs. This lack of response may be attributed to immune suppressive mechanisms, such as interferon signaling.

Dr. Joshua Bauml’s laboratory is studying pathways that block interferon signaling, such as the JAK-STAT pathway. He proposes to conduct a phase II combination clinical trial (the immunotherapy drug pembrolizumab with the JAK-STAT pathway inhibitor itacitinib) in patients with advanced-stage NSCLC. Dr. Bauml postulates that the combination regimen will remove the immune suppressive effects of interferon signaling and enhance the action of pembrolizumab. He will also be collecting tumor and blood samples during the course of the trial and characterize these samples to identify molecular predictors of response in patients.

Research Summary

Immunotherapy with PD-1 inhibitors can lead to very durable responses in metastatic non-small cell lung cancer, which was previously unheard of. Unfortunately, those who benefit constitute a relatively small subset of patients. Combining PD-1 inhibitors with other drugs to amplify response is an appealing strategy, but our understanding of how to do this rationally is quite limited. In addition, biomarker tests to predict who will benefit most from treatment are not very good at predicting responses. Our study aims to address both of these concerns.

Interferon signaling is a critical part of the body’s immune response to tumors, and can make it better or worse. If one thinks about interferon as a component of inflammation, this makes more sense: if you get sick, you want an inflammatory response to help get rid of the virus or bacteria making you ill. At the same time, if inflammation persists too long, it can hurt your body (as is seen in autoimmune conditions). Our team recently tried to take advantage of this concept in a mouse disease model, and found a way of combining PD-1 blockade with JAK inhibition (which stops interferon signaling), which led to remarkable anti-tumor responses in mice. We are currently running a study evaluating this same combination and dosing schedule in humans with non-small cell lung cancer.

In parallel with these efforts, we are developing a new biomarker to evaluate patients’ response to immunotherapy. Our group has recently found that we can identify a group of T cells that are “exhausted.” T cells are supposed to identify abnormal cells (like cancer) and get rid of them. Exhausted T cells, just like exhausted people, cannot do their job well. When patients receive a PD-1 inhibitor, their T cells can become “reinvigorated.” As one might imagine, if the T cells do not reinvigorate, they cannot kill the cancer cells.

Technical Abstract

Immunotherapy has transformed treatment for patients with lung cancer, but most patients still do not respond. Interferon signaling has a dichotomous role—without acute signaling, responses cannot occur, whereas persistent signaling can drive adaptive resistance. Our group recently reported in Cell that delayed administration of a JAK inhibitor in combination with immunotherapy can lead to enhanced treatment responses. We have opened a trial to test this approach, but also aim to improve patient selection and monitoring during immunotherapy by studying key parameters of T-cell exhaustion using peripheral blood flow cytometry. Our group recently showed that one could predict which patients would be most likely to respond to PD-1 blockade in this fashion.

Objective/Hypothesis

We hypothesize that in patients with metastatic non-small cell lung cancer (NSCLC) overexpressing PD-L1 (PD-L1=50%), treatment with pembrolizumab followed by delayed administration of itacitinib will improve the objective response rate. We will also measure the impact of this treatment on key parameters of T cell exhaustion and other biomarkers.

Study Design

This is an optimal three-stage trial of pembrolizumab and itacitinib for first-line treatment of PD-L1=50% metastatic NSCLC. Up to 48 evaluable patients with previously untreated metastatic NSCLC with tumor PD-L1=50% will be enrolled. Beginning with cycle 3 of pembrolizumab, the patient will receive itacitinib for 6 weeks. After 6 weeks of treatment with itacitinib, repeat imaging and tumor biopsy will be performed. Objective response by RECIST 1.1 will be determined based on this scan. Pembrolizumab monotherapy will then be resumed in the absence of progression. Serial blood and tumor samples will be used to monitor established biomarkers and markers of T-cell exhaustion using flow cytometry.

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Development of markers to predict response to immunotherapy in NSCLC

2018

Career Development Award

Jeffrey Thompson, MD

University of Pennsylvania

Philadelphia

Currently, three immune checkpoint inhibitors are approved by the FDA for the treatment of a subset of advanced-stage NSCLC. However, immunotherapy is a costly treatment regimen and comes with a unique side effect profile because of the inhibitors’ ability to cause inflammatory tissue damage. At present, the PD-L1 protein is used as a biomarker to predict which patients may respond to immunotherapy. Unfortunately, presence or absence of PD-L1 protein may not be an accurate predictor of response. Dr. Jeffrey Thompson is studying how we can develop more accurate biomarker signatures that may not only predict response to immunotherapy but may also determine which patients will develop treatment-related side effects. He will develop a novel blood-based liquid biopsy approach that will enable doctors to predict which patients will respond to immunotherapy drugs.

Research Summary

Lung cancer is the leading cause of cancer-related death in both men and women worldwide. The majority of patients initially present with late-stage disease with a 5-year survival rate as low as 5%. Improved understanding of how the immune system interacts with tumor cells has enabled the development of specific drugs that release the brakes off of the immune system allowing these immune cells to attack and kill cancer cells. These immunotherapeutic drugs have shown great promise for the treatment of lung cancer, but in the majority of clinical trials, only about 20-50% of patients respond. To date, measurement of a protein called PDL1 that is expressed on the tumor cell surface has been the most commonly used marker to predict which patients will respond to these therapies. However, even when high expressers of PDL1 are selected to receive immune targeted agents, less than half of patients respond. In addition, these novel drugs have significant economic costs and are associated with drug-related toxicities in 20-30% of patients. Thus, the goal of this proposal is to develop better predictors of response to immunotherapy in patients with lung cancer in order to avoid unnecessary toxicities, reduce costs, and enable a more appropriate therapy to be delivered. We will accomplish this goal in two complimentary specific aims. In Specific Aim 1, we have developed a novel method to quantitate a number of proteins expressed on immune and tumor cells present in the tumor microenvironment from late-stage lung cancer patients using a technique called multi-parametric flow cytometry. We hypothesize that quantifying these proteins will provide a more comprehensive view of the function of these immune cells with the tumor and be able to predict which patients will respond to immunotherapy. In Specific Aim 2, we will focus on a newly developed blood-based biomarker, exosomal PDL1 expression, to predict response to immunotherapy. We will enroll late-stage non-small cell lung cancer patients scheduled to receive an immunotherapeutic agent who will undergo additional tumor biopsies and blood draws for analysis, and patients be followed over time to monitor for response and outcome data.

Technical Abstract

This project describes a 3-year training program for a career as a physician-scientist with the long term goal of establishing a research program within the field of translational thoracic oncology. The applicant is currently an Instructor of Medicine in the Section of Interventional Pulmonology and Thoracic oncology conducting research in developing biomarkers for the treatment selection and monitoring of patients with lung cancer. The research focus of this proposal is to develop molecular markers to better identify the subgroup of patients that will respond to PD1/PDL1 therapies in order to avoid unnecessary toxicities, reduce costs, and enable more appropriate therapies to be delivered. This goal will be accomplished in two complementary specific aims. In Specific Aim 1, a novel approach to acquire fresh tissue samples for immunophenotyping will be utilized to prospectively determine the ability of deep T cell phenotyping and functional assays to predict response to anti-PD1/PDL1 therapy using multi-parametric flow cytometry. In Specific Aim 2, a newly developed technique that enables the quantitative measurement of circulating PDL1 exosomes will be utilized to determine the association of pretreatment and on-treatment exosomal PDL1 expression levels to predict clinical outcomes in non-small cell lung cancer patients receiving checkpoint blockade. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures in thoracic oncology/tumor immunology, acquisition of advanced laboratory techniques, and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of the Thoracic Oncology Laboratory at the University of Pennsylvania and Co-Director of the Abramson Cancer Center’s Translational Center of Excellence for Lung Cancer Immunobiology, and Dr. Anil Vachani who is the Director of Clinical Research for the Section of Interventional Pulmonology and Thoracic Oncology at Penn. Dr. Albelda and Dr. Vachani have mentored over 100 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award.

Key words

Biomarker or biomarker testing

Immune checkpoint inhibitors

Immunotherapy

Metastatic

Non-small cell lung cancer (NSCLC)

Stage III

Stage IV

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Genetic regulation and therapeutic correction of immune escape in lung cancer

2008

Therapeutics Award

Funded equally by LUNGevity Foundation and the American Lung Association

George C. Prendergast, PhD

Lankenau Institute for Medical Research

Wynnewood

The IDO protein stops immune cells from recognizing cancer cells and mounting an attack against the cancer. Dr. Prendergast is determining how the IDO protein works in non-small cell lung cancer cells that have mutations in the KRAS gene. He is also testing new compounds that can inhibit IDO in non-small cell lung cancer.

Key words

Adenocarcinoma

Chemotherapy

Immunotherapy

Non-small cell lung cancer (NSCLC)

Targeted therapy

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Role of CAV-1 in Supressing Lung Tumor Formation: Therapeutic Implications

2008

Therapeutics Award

Funded equally by LUNGevity Foundation and the American Lung Association

Michael P. Lisanti, MD, PhD

Thomas Jefferson University

Philadelphia

Genes that can suppress the development of tumors are often lost or silenced during the development of human lung tumors. Because they function as a “brake” that normally prevents the onset of lung tumors, they provide new targets for the development of replacement therapies for the effective treatment of lung cancers. Dr. Lisanti is testing the effectiveness of the replacement of a novel tumor suppressor gene, caveolin-1.

Key words

Adenocarcinoma

Non-small cell lung cancer (NSCLC)

Targeted therapy

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Folate-related biomarkers as predictors of response to pemetrexed therapy

2011

Therapeutics Award

Alexander Steven Whitehead, DPhil

University of Pennsylvania

Philadelphia

Pemetrexed is a chemotherapy drug commonly used for the treatment of non-small cell lung cancer. The drug blocks two proteins called DHFR and TS that cancer cells need to grow. Not all patients respond to pemetrexed. Dr. Alexander Whitehead is studying how changes in the DHFR and TS genes predict response of non-small cell lung cancer patients to pemetrexed.

Research Summary

Folate is a B vitamin that is very important for maintaining health and for protecting against a range of major diseases. It is obtained as ‘natural’ folate from food, in particular leafy green vegetables, or as the synthetic form folic acid from supplements and products made with fortified flour. There are genetic differences in the enzymes that control the way that folate is used inside cells; folate is actually present as multiple forms that support different biochemical processes, and these differences confer different levels of susceptibility to diseases that are associated with low folate and altered folate metabolism. Some of the genetic differences have been linked to lung cancer, and some have recently been linked to good responses to pemetrexed, an anti-folate drug that is used to treat lung cancer. The goal of this project is to define the main folate-related genetic variants AND the relative amounts of the different forms of folate inside cells in patients with lung cancer, and to establish whether any of these factors are over-represented in (i) lung cancer patients compared to healthy individuals, and, even more importantly, in (ii) lung cancer patients who show superior responses to pemetrexed. The project has the potential to identify genetic markers and/or biomarkers that could be used to guide lung cancer chemotherapy.

Technical Abstract

Folate/homocysteine (Hcy) metabolism facilitates the methylation of DNA, proteins and carcinogens; nucleic acid synthesis; and glutathione generation. Dysregulation of folate/Hcy metabolism, due to suboptimal vitamin status and/or functional polymorphisms of key enzymes, is an etiologic feature of some cancers, including lung cancer. Several drugs that target enzymes of folate/Hcy metabolism have become mainstays of cancer chemotherapy, most recently pemetrexed (PMX), which targets dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and is used to treat patients with non-small cell lung cancer (NSCLC). Our primary and secondary hypotheses are that folate/Hcy phenotype, perhaps underpinned by genotype, is a major contributor to (i) clinical response to PMX, and (ii) risk of NSCLC itself. We will use archived and newly acquired samples from PMX-treated NSCLC patients to define pre-treatment and in-treatment folate/Hcy phenotypes using LC-MRM/MS technology that can precisely determine the concentrations and relative proportions of key folates (tetrahydrofolate; 5-methyltetrahydrofolate; 5,10-methenyltetrahydrofolate) and Hcy. Genotypes will be determined for approximately twenty folate-related genes. Biostatistical analyses will be used to establish

whether aspects of folate/Hcy phenotype and/or genotype are prospectively or concurrently associated with time to tumor progression, survival time, toxicity, etc. Case-control analysis of genetic and phenotypic data will also be undertaken to determine whether any genetic and/or biomarker variables predict case status. This project has the potential to identify biomarkers and/or genetic factors that can be used to predict or monitor responses of NSCLC patients to PMX, and may provide the basis for the future deployment of personalized medicine strategies in lung cancer treatment.

Key words

Adenocarcinoma

Biomarker or biomarker testing

Chemotherapy

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Stage IV

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Targeting KRAS-mutant NSCLC through inhibition of MTOR and Hsp90

2013

Career Development Award

Timothy F. Burns, MD, PhD

University of Pittsburgh Cancer Institute

Pittsburgh

Dr. Burns is working on targeted therapy for NSCLC patients with mutations in a gene called KRAS, using a new class of drugs.

Research Summary

Lung cancer is the leading cause of cancer death in the United States and worldwide. In non-small cell lung cancer (NSCLC), a protein called KRAS often becomes inappropriately turned on and causes a tumor to grow. Patients with KRAS-mutated lung cancer have a poor prognosis and no current therapies target this critical oncogene. Our goal is to develop novel therapies for patients with KRAS mutant lung cancer. In this proposal, we focus on a therapy that can inhibit multiple signaling pathways downstream of KRAS that are required for KRAS mutant tumors to grow. We have found in a clinical trial that some of the KRAS mutant tumors shrink when treated with a novel Hsp90 inhibitor, ganetespib. In Aim 1 of this grant we will identify what makes some KRAS mutant tumors respond initially to ganetespib and then become resistant. These studies will identify targeted therapeutics agents that could be combined with ganetespib to overcome resistance to ganetespib alone. Furthermore, we have recently shown that the combination of an Hsp90 inhibitor, ganetespib, and an mTOR inhibitor is effective in KRAS mutant tumor cell lines. In Aim 2, we will examine candidate biomarkers of response to this combination so that we can test these biomarkers in the third aim of our grant, a Phase I/II clinical trial of the combination of ganetespib and an mTOR inhibitor in patients with KRAS mutant NSCLC. This translational approach will allow us to target this combination to the patients who are likely to respond.

Technical Abstract

A significant fraction of NSCLC have mutant KRAS which predicts poor response to cytotoxic therapy and portends a poor prognosis. Despite the discovery of the first mutation in the KRAS oncogene in NSCLC over two decades ago, there are no current therapies targeting this critical oncogene. In this proposal we explore a novel and exciting therapeutic strategy to target KRAS-mutant NSCLC through the combination of Hsp90 and mTOR inhibition. We have preclinical evidence suggesting that the combination of ganetespib and an mTOR inhibitor may be an effective therapeutic strategy for patients with KRAS- mutant NSCLC. In Aim 1, we will define resistance mechanisms to single-agent ganetespib in KRAS- mutant NSCLC. The identification of resistance mechanisms to single-agent ganetespib will reveal novel pathways that we can then target in combination with an Hsp90 inhibitor. In Aim 2, we will test the hypothesis that activation of the mTOR pathway through alterations in STK11 or PI3KCA mutations will predict response to the combination. Finally, in Aim 3 we will translate our studies to the clinic in a phase I/II trial of the combination of ganetespib and an mTOR inhibitor in patients with advanced KRAS-mutant lung adenocarcinoma. Importantly, we will have correlative studies looking at response in subpopulations of KRAS-mutant tumors that are hyperactive for the mTOR pathway (STK11, PIK3CA mutations). This translational approach will allow us to identify biomarkers that we can use to effectively target this combination to the patients with greatest chance to benefit from this therapy.

Key words

Acquired resistance

Adenocarcinoma

Biomarker or biomarker testing

Heat shock protein

KRAS

mTOR

Non-small cell lung cancer (NSCLC)

PI3 kinase

Targeted therapy