2011:
2010:
2011
Clinical Fellow Research Award
Sensitization and Rapid, Noninvasive Assessment of Lung Cancer Response to Therapy
Posted November 15, 2011
Arif N. Ali, M.D., Emory University
Non-small cell lung cancer is generally treatable with surgery, radiation, and/or chemotherapy. Currently, the effectiveness of treatment cannot be accurately assessed until several months after its completion, introducing a significant delay regarding treatment decisions should the patient fail to respond. To address this challenge Dr. Arif Ali is working on developing a PET imaging modality that will indicate likely tumor response to a given treatment within the first few days of administration. Dr. Ali hypothesizes that the tumor expression of GRP78, a protein whose expression level has been associated with chemotherapy response, can be non-invasively measured and monitored to assess tumor response to chemotherapy or radiation. Dr. Ali is currently confirming whether GRP78 levels correlate with chemotherapy and radiation treatment in patient samples and developing a PET tracer conjugated with a peptide with specific affinity for GRP78. The correlation of PET-GRP78 tumor uptake with chemotherapy and radiation response will be assessed in animal models.
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Concept Award
Innovative Strategy for Treatment of Lung Cancer: Inhalatory Codelivery of Anticancer Drugs and siRNA for Suppression of Cellular Resistance
Posted November 15, 2011
Dr. Oleh Taratula, Ph.D. and Dr. Tamara Minko, Ph.D. Rutgers University
Insufficient chemotherapeutic efficacy may be one of the main reasons for the poor prognosis in patients diagnosed with lung cancer, which takes more lives each year than all other major cancers combined. Systemic administration of chemotherapy can result in several severe adverse side-effects, and the dose is often limited to what the patient can tolerate rather than what is needed to kill the cancer. Moreover, tumors often rapidly develop drug resistance upon exposure via "pump" (i.e., active drug efflux from tumor cells) or "nonpump" (i.e., anti-apoptotic defense of tumor cells) mechanisms. Drs. Oleh Taratula and Tamara Minko have sought to overcome these issues by developing a novel inhalable drug delivery system composed of biocompatible nanoparticles conjugated with a tumor-targeting peptide, anti-cancer drugs (doxorubicin or cisplatin), and siRNAs as suppressors of cellular drug resistance. Testing in mice has demonstrated that nanoparticles impregnated with therapeutic agents show lung tumor-specific accumulation after inhalation along with limited systemic toxicity and adverse side effects to healthy organs. Based on these results, Investigators plan on conducting additional studies to further develop this system for lung cancer treatment.
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A Novel Therapeutic Target for Squamous Cell Lung Cancer
Posted July 19, 2011
Peter Hammerman M.D., Ph.D., Dana-Farber Cancer Institute, Boston, Massachusetts
While lung cancer continues to be the principal cause of cancer-related deaths in the United States, treatment of lung adenocarcinomas with inhibitors of the epidermal growth factor receptor tyrosine kinase or the anaplastic lymphoma kinase has led to remarkable responses in a subset of lung adenocarcinoma patients whose tumors harbor genetic alterations in either of these kinases. However, little progress has been made in the treatment of lung cancer patients with lung squamous cell carcinoma (SCC), the second most common type of lung cancer. Dr. Peter Hammerman, recipient of an FY09 LCRP Clinical Fellow Research Award, is currently identifying and characterizing novel therapeutic targets for SCC by utilizing a functional genomic approach. Dr. Hammerman has identified the discoidin domain receptor 2 (DDR2) kinase gene as a target of recurrent somatic mutations in squamous lung tumors; therefore, Dr. Hammerman is focusing his efforts on characterizing whether DDR2 is a therapeutic target for the treatment of SCCs. In his recent publication in Cancer Discovery, the flagship journal of the American Association of Cancer Research, he identified 11 novel mutations in DDR2 from 290 human SCC samples with a mutation frequency of 3.8%. In addition, he found that dasatinib, a drug currently used for leukemia, can inhibit the proliferation of DDR2-mutated SCC cell lines both in vitro and in vivo. This suggests that DDR2 may be the first therapeutic target in lung SCC with existing clinically approved drugs, thus leading the way for clinical trials testing the efficacy of tyrosine kinase inhibitors for lung SCCs. Dr. Hammerman plans to open a trial of dasatinib for squamous cell lung cancer patients later this year.
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2010
Optimizing MET-Targeted Therapy for Lung Cancer Personalized Treatment
Posted November 19, 2010
Patrick Ma, M.D., M.Sc., Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
Lung cancer is the leading cause of cancer death in both men and women. Targeted therapies that focus on molecular and cellular changes that are specific to lung cancer have shown some success, such as the use of erlotinib in metastatic lung cancer that targets the cancer-associated protein epidermal growth factor receptor. However, all initial responders to this targeted drug eventually progress and succumb to resistant recurrent disease. For targeted therapy to be ultimately successful and improve patient survival and long-term outcome, two critical steps need to be achieved: (1) Enhancement of the initial tumor therapeutic response to the treatment regimen (overcome de novo resistance), and (2) abolishment of the mechanism of tumor-resistant-escape to therapy that forms the basis of future resistant disease relapse (overcome acquired resistance). Dr. Patrick Ma, recipient of a Fiscal Year 2009 Lung Cancer Research Program Promising Clinician Award, will address these two issues in his investigation of the MET receptor as a therapeutic target in lung cancer. Preliminary findings from Dr. Ma's laboratory demonstrate that tumors can escape the effects of a MET inhibitor during a brief window of time in which molecular changes occur, thus making them resistant to treatment. Dr. Ma will combine molecular imaging of small animals with immunohistochemical analysis to investigate the potential use of clinical MET inhibitor drug XL184 as an avenue for personalized targeted lung cancer therapy. Specifically, he will also study the role of MET mutations as the molecular factors that may predict response and resistance to the inhibitor drug. Additionally, the cell signaling pathways that determine cell fate when tumors are treated with MET inhibitor will be explored. This project will provide improved strategies to diminish early tumor resistance in tumor cells and offer a novel way to improve long-term clinical outcome and survival in lung cancer patients.
Links:
Public and Technical Abstracts: Optimizing MET-Targeted Therapy for Lung Cancer Personalized Treatment
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Enabling Highly Sensitive Detections of Multiple Lung Cancer Biomarkers Using Nanoparticles
Posted November 10, 2010
Ming Su, Ph.D., University of Central Florida, Orlando, Florida
Early detection of lung cancer is crucial for treatment and survival. Although there are over one hundred biomarkers associated with lung cancers, a major challenge exists for biomarker-based early detection of lung cancers because most biomarkers are not effective, have low concentrations, exist at different stages, and need extensive effort to prepare samples. One approach to enhance diagnostic accuracy is to use multiple lung cancer biomarkers, where even if each biomarker has low power, their combination can provide accurate information. To detect cancer biomarkers, a number of nanoparticles with unique optical, electric, magnetic, or electrochemical properties have been used. Further, nanoparticle-based detections have achieved extremely high sensitivity via the conversion of biological recognition events into measurable physical signals that can be amplified. Nanoparticle-based methods are limited, however, due to their low multiplicity, as only one or several types of biomarkers can be detected at one time, and screening one sample for multiple biomarkers requires extensive time and effort. Thus, to enhance detection, Dr. Ming Su, recipient of a Fiscal Year 2009 Lung Cancer Research Program Concept Award, will develop a new technique for highly sensitive detection of multiple protein biomarkers using encapsulated phase change nanoparticles of differing metals or alloys as thermal barcodes. It is anticipated that the high multiplicity, sensitivity, and reliability of the unique alloy nanoparticles will allow the early detections of multiple cancer biomarkers in small amounts of sample, thereby ensuring effective treatment of lung cancer patients.
Figure: Protein biomarker (2) detection using encapsulated phase change nanoparticles (3) and magnetic bead separation (1)
Links:
Public and Technical Abstracts: Encapsulated Solid-Liquid Phase Change Nanoparticles as Thermal Barcodes for Highly Sensitive Detections of Multiple Lung Cancer Biomarkers
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