Alexander Drilon, MD
Medical Oncology Fellow, Memorial Sloan-Kettering Cancer Center
One of the ways tumors can grow and spread is by blocking a person’s immune system from recognizing and destroying tumor cells. Drugs are now being developed that can overcome this block, allowing a person’s own immune system to start attacking the tumor. One such immune boosting drug, BMS-936558, has shown promise at treating patients with advanced non-small cell lung cancer. However, this drug does not work for all patients. Dr. Drilon’s goal is to identify which patients are most likely to benefit from this therapy.
Dr. Drilon’s grant will fund a clinical trial to investigate whether patients with a specific tumor biomarker will be more likely to respond to BMS-936558 compared to patients without the biomarker. In addition, he will investigate other biomarkers that may predict response to this drug.
Non-Technical Abstract – Phase II and Biomarker Study of BMS-936558 in PI3K-Active Non-Small Cell Lung Cancers
Patients with advanced non-small cell lung cancers are incurable with currently available therapies. For the first time, however, drugs that work by boosting the immune system such as BMS-936558 have provided a glimpse into the possibility of long-term responses and potential cure for a small percentage of patients with advanced disease. BMS-936558 is active against non-small cell lung cancers, with some patients continuing to benefit from the drug well beyond one year.
To maximize these successes, we must be able to identify patients who will benefit the most from BMS-936558. Studies suggest that non-small cell lung cancers with potential activation of a growth pathway called the PI3 kinase pathway may be more susceptible to treatment with the drug. Our clinical experience at Memorial Sloan-Kettering supports this observation: patients with evidence of PI3 kinase activation have had dramatic responses to BMS-936558 both in combination with chemotherapy and with the drug alone as maintenance therapy.
This phase 2 clinical trial is the first study of its kind to give BMS-936558 to patients with advanced non-small cell lung cancers with evidence of an active PI3 kinase pathway. Our hypothesis is that these patients will be more likely to respond to BMS-936558 compared to unselected patients. In addition, we are also looking at other markers that may predict response to this drug, such as the changes in immune cells that occur after treatment with BMS-936558.
A Breath of Hope Lung Foundation is proud to partner with National Lung Cancer Partnership and has disbursed $54,000 in support of this project (February 2013).
2012 Projects and earlier
Trever Bivona, MD PhD
Assistant Professor, University of California, San Francisco
Approximately 20% of non-small cell lung cancers have mutations in a gene called EGFR (epidermal growth factor receptor). While a drug called erlotinib (Tarceva®) appears especially effective in controlling these tumors, most tumors become resistant to the effects of the drug over time. These patients’ drug resistance can be promoted by the activation of a gene called AXL, so Dr. Bivona’s research seeks to understand how AXL promotes erlotinib resistance. This project could lead to clinical trials that determine whether drugs that block AXL can improve erlotinib¹s effectiveness, helping patients on the drug live longer. A Breath of Hope Lung Foundation is proud to partner with the National Lung Cancer Partnership on funding this project. $108,000 was disbursed in 2012 and 2013 in support of this project.
Title of Project: PARP1 as a novel therapeutic target in small cell lung cancer
There is an urgent, unmet need for more effective treatments for patients with small cell lung cancer (SCLC), a highly lethal malignancy with an incidence rate similar to that of ovarian cancer or glioblastoma. Recently we discovered that poly (ADP-ribose) polymerase 1 (PARP1), a protein that repairs damaged DNA, is dramatically overexpressed in SCLC and that SCLC cells are killed by treatment with drugs that inhibit PARP1. We predict that PARP inhibition may increase the activity of chemotherapies that act by damaging the DNA of cancer cells. Therefore, we designed a clinical trial to test the combination of a PARP inhibitor (ABT-888) with chemotherapy (TMZ) in SCLC patients who have progressed despite receiving one or more standard chemotherapy regimens. In this project, we will develop potential tumor and blood biomarkers that can predict those patients most likely to benefit from this therapy. Our results are directly applicable to the clinic and will lead to more personalized therapeutic strategies for proteins battling this deadly disease. Preliminary data garnered through these studies will be invaluable for future planned clinical trials of PARP inhibitors in SCLC and potentially in other malignancies, such as breast and ovarian cancer, where these drugs have shown clinical activity. A Breath of Hope Lung Foundation is proud to partner with LUNGevity on funding this and other research projects. $55,000 was disbursed for this 2011-2012 project.
Title of Project: Predictive blood-based markers of response to VEGF inhibitors in NSCLC
Research Summary: Predictive blood-based markers of response to VEGF inhibitors in NSCLC
Drugs that target tumor blood vessels, such as bevacizumab and other inhibitors of the VEGF pathway, have improved survival in patients with advanced NSCLC, but only a subset of patients benefit significantly from the drugs while others experience no benefit or even life-threatening toxicities. Furthermore, almost all NSCLC tumors eventually become resistant to these treatments. There is therefore a critical unmet need for biomarkers to identify which patients will benefit from a VEGF inhibitor (predictive markers) and to understand how tumors become resistant to these agents. A major challenge for developing these markers is that tumor angiogenesis is promoted by circulating cytokines and angiogenic factors (CAFs) that may be produced by the tumor as well as the host. Therefore, it is likely that predictive markers for VEGF inhibitors may reflect both influences. For this reason, we hypothesize that by comprehensively profiling angiogenesis-related CAFs and other peptides in the blood, as well as germline variations in angiogenesis-related genes, predictive markers for identifying which patients benefit from VEGF inhibitors (alone or with chemotherapy) can be developed and validated. The PIs of this proposal have already conducted studies establishing three promising and potentially complementary approaches to identify predictive markers using blood samples: 1) multiplex CAF profiling; 2) proteomic analysis using mass spectroscopy (MALDI-TOF); and 3) a signature of single nucleotide polymorphisms (SNPs) in three angiogenesis genes. In this proposal, these three approaches will be tested using samples from completed clinical trials of VEGF inhibitors in NSCLC patients; the most promising markers will then be validated using samples from two independent randomized trials. These studies have the potential to significantly advance the treatment of NSCLC patients by identifying which patients are most likely to benefit from a VEGF inhibitor, and by sparing patients who are unlikely to benefit from these drugs. They can also provide critical insights into mechanisms of resistance that can guide future combination regimens. $55,000 was disbursed by A Breath of Hope Lung Foundation in 2011 to support this project.