Improving Existing Treatments for Non-Small Cell Lung Cancer
Tarceva® (erlotinib) is a drug used to treat a form of lung cancer most often seen in non-smokers, which carries an activated copy of a gene called EGFR. Signals from EGFR control growth, invasion and survival of tumor cells. However, patients frequently develop resistance to Tarceva, which works by inhibiting EGFR. DR. ESTHER P. BLACK is examining whether a dual targeted therapy consisting of EGFR and MEK inhibition will improve responses and reduce acquired resistance to drugs like Tarceva.
A major problem that arises is resistance to drugs that block EGFR. DR. SIZHI PAUL GAO is attempting to get around this by exploring other proteins in the tumor cell that drive its growth. These proteins are called IL6 and Stat3. He will test whether lung cancer cells that are resistant to EGFR inhibitors can still form tumors in mice when IL6 and Stat3 are blocked.
DR. E. AUBREY THOMPSON studies a protein called phospholipase D1 (PLD1). He has observed that inhibition of PLD1 results in death of lung cancer cells that are dependent on EGFR even when they are resistant to EGFR inhibitors. He will determine whether drugs that can inhibit PLD1 cooperate with EGFR inhibitors to improve the killing of tumor cells.
The map kinase pathway is a chain of reactions that results in uncontrolled growth of lung cancer cells. EGFR and MEK are links in this chain. Some patients have tumors that depend on another link called RAF. DR. POULIKOS POULIKAKOS is investigating the regulation of the chain reaction by using drugs that specifically inhibit RAF.
Targeting drugs efficiently to the tumor cells is an important aspect of treatment. DR. RAJAGOPAL RAMESH is investigating a novel technology not only for efficient drug delivery but also for imaging. He will use tiny particles called nanoparticles that are not visible to the naked eye. The targeted imaging and therapeutic (IMAT) nanoparticles are composed of an iron core coated with gold, which is useful for magnetic resonance imaging (MRI). The surface of the nanoparticles are coated with the EGFR-targeted drug, cetuximab, which should attack EGFRexpressing lung cancer cells and produce a therapeutic effect that can be monitored non-invasively by MRI.
Predicting Patient Responses to Therapies Toward a More Personalized Medicine
Like all tissues, tumors depend on a blood supply and nutrients in order to grow. A class of drugs known as anti-angiogenics works by blocking this nutritional supply and starving the tumor. However, only a subset of patients responds to this type of therapy. DR. ROLF A. BREKKEN is comparing the genetic makeup of lung cancer cells from responsive and unresponsive patients. The hope is that he may uncover differences which could be used to predict which patients are more likely to respond to anti-angiogenic therapy.
Tarceva (erlotinib) and Iressa (gefitinib) are drugs that are used to treat lung cancer, but a patient’s response to these drugs seems to be linked to whether the tumors carry changes in two genes, KRAS and EGFR. However, it has been difficult to test patient tumors for these changes, because it is often not feasible to obtain tissue specimens. DR. PHILIP MACK will gather evidence to determine if patient blood samples bear traces of these alterations and whether they could be used to predict responsiveness to these treatments.
Exploring New Avenues for Treatment – Uncoering other Players In the Development of Lung Cancer
DR. WENRUI DUAN is treating lung cancer in mice with a novel anti cancer drug called PRIMA-1. Many lung cancer cells have a defective copy of the p53 gene that normally restricts cell growth. PRIMA-1 may have the potential to preferentially destroy cells with defective p53 and restore normal p53 function, thereby restraining runaway tumor growth.
With the goal of finding new treatments to make tumors less invasive, DR. RANDOLPH HASTINGS is trying to determine why some lung cancers grow more aggressively than others. Tumor cells are embedded in a mesh of proteins called the matrix. Aggressive tumors break free of the matrix and invade the surrounding tissue, while less aggressive ones remain more confined. He will examine whether a certain hormone, called PthrP, controls the integrins, which are components of the cancer cell that attach to the surrounding matrix. If this is so, modulating PthrP levels and altering the tumor cells’ interaction with the matrix may lead to less aggressive growth.
DR. WILLIAM KIM is studying the role of the LKB1 and HIF-1 genes in lung cancers. HIF is a protein involved in the growth of tumor blood vessels as well as the metastatic spread of tumors. HIF is activated when the LKB1 gene is lost, an event which occurs in up to one-third of non-small cell lung cancer cases. Dr. Kim seeks to determine if HIF is responsible for the poor prognosis of patients with LKB1 loss. His findings will have immediate implications for the treatment of lung cancer through the use of FDA-approved inhibitors of the HIF pathway.
DR. FAYE JOHNSON has preliminary evidence that a protein called EphA2, which is expressed on the surface of some lung cancer cells, could play a role in tumor progression. In other types of cancers, reducing the level of EphA2 results in smaller tumors and less invasive disease. She will test whether interfering with EphA2 function affects the properties of lung tumor cells, and evaluate whether anti-EphA2-targeted therapy may be useful.
DR. RACHEL LINGER’S research is focused on the role of a protein called Axl in lung cancer, which makes the cells more invasive and increases the chance that the cancer will spread. These tumor cells may also be more resistant to killing with chemotherapy. She will test whether inhibitors of the Axl protein increase the effectiveness of chemotherapy drugs, and limit invasiveness of lung cancer cells. If proven correct, these findings could lead to a more effective treatment for lung cancer.
EGFR and HER-2 are two culprits that often cause the uncontrolled growth of lung cancer cells. DR. LYNNE REGAN proposes to develop novel methods to prevent these proteins from being made in the cell. These studies could provide a better understanding of the nature of the disease and enable progress towards developing novel therapeutic treatments.
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