Rajagopal Ramesh Ph.D.

Recipient of the Felice Lipit Jentis Memorial/Joan’s Legacy Research Grant. Funded equally by Joan's Legacy and The Felice Lipit Jentis Memorial BAC Research Trust.

Lay Description

Progress in understanding the molecular cause of lung cancer has resulted in the identification of the epidermal growth factor receptor (EGFR) as an important player in lung tumor cell creation, survival and spread of disease. Thus, elimination or reduction of EGFR expression in lung cancer cells using EGFR-targeted drugs will lead to cancer cell death. Based on this concept several EGFR-targeted anticancer drugs have been developed and are currently under testing for lung cancer. A drawback of EGFR-based therapy, as with other therapies, is the possibility that patients will develop a resistance to treatment. However, current treatment techniques do not allow for a rapid and noninvasive determination of whether lung cancer patients receiving EGFR-based therapy are responding to treatment and when it is appropriate to discontinue therapy when the patient is responding. As a result, patients with lung cancer may receive an ineffective treatment for extended periods of time.

To overcome the current limitations of cancer-targeted therapies and improve the health of patients with lung cancer, the development and application of biomedical technologies, such as nanotechnology and nanomaterials, are warranted. Nanotechnology refers to the development and use of small molecules referred to as nanoparticles that are nanometers in size and not visible to the naked eye. The nanoparticles can be designed for delivering anti-cancer drugs specifically to cancer cells, thereby minimizing toxicity to normal tissues; carry molecules that will enable detection of cancer cells by molecular imaging noninvasively without surgery; and also determine response to treatment rapidly and noninvasively by imaging. Thus, the application of nanotechnology will enable clinicians in rapidly determining the anti-cancer drug delivery to cancer cells and the beneficial response to treatment, providing a new standard for lung cancer treatment in the clinic. There have been several reports demonstrating the effectiveness of nanoparticles for molecular imaging, drug delivery, or therapy of cancer. However, nanoparticles that possess multifunctional properties (e.g., achieving both molecular imaging and treatment of lung tumors using the same nanoparticles) have yet to be reported; therefore, the development and testing of multifunctional nanoparticles are warranted.

In the submitted research application, we proposed laboratory studies to test a novel tumor-targeted imaging and therapeutic (IMAT) multifunctional nanoparticle in human lung cancer cell lines, especially of bronchioalveolar carcinoma and adenocarcinoma histology. The IMAT nanoparticles are composed of a superparamagnetic iron core coated with gold, creating an iron-oxide/gold mixture useful for magnetic resonance imaging (MRI) and optical imaging. A clinically approved EGFR-targeted drug, cetuximab, is coated on the surface of the gold nanoparticles, which serve as both a targeting and a therapeutic agent for lung cancer. We hypothesize that our tumor-targeted IMAT multifunctional nanoparticles will selectively target EGFR-expressing lung cancer cells and produce a therapeutic effect that can be monitored noninvasively by MRI.

Our results from the proposed studies will lead to advanced preclinical studies and translate to clinical testing of the tumor-targeted IMAT multifunctional nanoparticles for the treatment of lung cancer, as well as other cancers.

Scientific Abstract

Epidermal growth factor receptor (EGFR) is an important player in lung tumor cell proliferation, survival, and metastasis. Previous studies have found that EGFR expression is higher in lung cancer cells than in normal cells. EGFR expression amplifies the cell survival signals mediated by binding of the ligand (EGF) to its receptor (EGFR). Furthermore, EGFR gene mutations that amplify the cancer survival signal have been detected in the adenocarcinoma and adenocarcinoma with bronchioalveolar carcinoma (BAC) histologic subtypes, which account for 70-80% of non-small cell lung cancers (NSCLCs). Thus, EGFR has been identified as a therapeutic target, and synthetic small-molecule inhibitors (gefitinib, erlotinib) and biologic agents (cetuximab) targeting EGFR have been developed for the treatment of lung cancer, as well as other cancers.

Patients with lung adenocarcinoma, particularly those with non-mucinous BAC histology, have achieved clinical responses in studies testing the efficacy of EGFR inhibitors (gefitinib, erlotinib). Furthermore, most clinical responses were observed in patients with no history of smoking. A molecular analysis of tumors from patients who achieved a clinical response showed that the tumors often harbored EGFR mutations. Previous studies have also found that a small number of lung cancer patients without the EGFR mutation also responded to treatment with EGFR inhibitors, indicating that EGFR inhibitor-based therapy should be administered to all patients with lung cancer regardless of the patient’s EGFR mutational status. A potential drawback of EGFR-based therapy, as with other therapies, is the possibility that patients will develop a resistance to treatment. For example, some patients who initially responded to gefitinib or erlotinib therapy have developed a resistance to these therapies after prolonged treatment. However, current treatment techniques do not allow for a rapid and noninvasive determination of whether patients receiving EGFR-based therapy are responding to treatment and when it is appropriate to discontinue therapy when the patient is not responding. As a result, patients with lung cancer may receive an ineffective treatment for extended periods of time. Another major clinical problem is the inability to demonstrate whether the EGFR-targeted inhibitors specifically targeted the lung tumors to produce the desired therapeutic effect.

To overcome the current limitations of cancer-targeted therapies and improve the health of patients with lung cancer, the development and application of biomedical technologies, such as nanotechnology and nanomaterials are warranted. The development of nanotechnologies to noninvasively monitor tumor-targeted drug delivery and rapidly determine therapeutic response will provide a new paradigm for lung cancer treatment in the clinic. There have been several reports demonstrating the effectiveness of nanoparticles for molecular imaging, drug delivery, or therapy of cancer. However, nanoparticles that possess multifunctional properties (e.g., achieving both molecular imaging and treatment of lung tumors using the same nanoparticles) have yet to be reported; therefore, the development and testing of multifunctional nanoparticles are warranted.

We propose to test a novel tumor-targeted imaging and therapeutic (IMAT) multifunctional nanoparticle in human lung cancer cell lines of BAC and adenocarcinoma histology. The IMAT nanoparticles are composed of a superparamagnetic iron core coated with gold, creating an iron-oxide/gold hybrid useful for magnetic resonance imaging (MRI) and optical imaging. A clinically approved anti-EGFR antibody (cetuximab) is coated on the surface of the gold nanoparticles, which serve as both a targeting moiety and a therapeutic agent. We hypothesize that the tumor-targeted IMAT multifunctional nanoparticles will selectively target EGFR-expressing lung cancer cells and produce a therapeutic effect that can be monitored noninvasively by MR imaging. To test our hypothesis we have identified two specific aims: Specific Aim 1: Molecular characterization of tumor-targeted imaging and therapeutic (IMAT) multifunctional nanoparticles against human lung adenocarcinoma and bronchioalveolar carcinoma cell lines and comparison to normal cell lines in vitro. Specific Aim 2: Determine the molecular imaging capabilities and therapeutic efficacy of tumor-targeted IMAT multifunctional nanoparticles against human lung adenocarcinoma and bronchioalveolar carcinoma xenografts in vivo.

Our results from the proposed studies will lead to advanced pre-clinical studies and translate to clinical testing of the tumor-targeted IMAT multifunctional nanoparticles for the treatment of lung cancer, as well as other cancers.