Research and Clinical Trials
- Can radiolabeled organism-specific antibodies be effective in killing microbial cells and what are the radiobiological and immune mechanisms of this killing?
- Can melanin being an intracellular antigen serve as target in radioimmunotherapy of metastatic melanoma?
- Can high doses of positrons (anti-particles for electrons) delivered by standard Positron Emission Tomography agent 18-Fluorine-labeled glucose (FDG) be therapeutic in metastatic metabolically active cancers?
Development of RGD Peptidomimetic libraries for Glioblastoma Multiforme.
Nanoparticle libraries for rhabdoid tumor imaging and therapeutics.
- Clinical Value of PET-CT in Squamous Cell Carcinoma of the Head and Neck
- Sodium/iodide Symporter (NSI) and Radioiodide Therapy in Metastatic Breast Cancer
- Principal Investigator for Multicenter Trial (involving Montefiore Medical Center, Weill-Cornell and Mt. Sinai School of Medicine) entitled: The Incremental Value of Attenuation Correction on the Diagnostic Accuracy of Stress Radionuclide Myocardial Perfusion Imaging (IVAC). 2002-ongoing.
- Principal Investigator at Montefiore Medical Center for multicenter trial: A Phase III, Randomized, Double-Blind Study of Intravenous CVT-3146 vs. Adenoscan in Patients Undergoing Stress Myocardial Perfusion Imaging. Sponsor: CV Therapeutics, Inc. 2003-2005.
- Principal Investigator at Montefiore Medical Center for: An open-label, multicentre, phase 3 study evaluating the prognostic usefulness of I123-mIBG scintigraphy for identifying subjects with heart failure who will experience an adverse cardiac event. 2005-ongoing.
- Co-investigator: Comparison of 64-slice multidetector coronary CT angiography with stress SPECT Radionuclide Myocardial Perfusion Imaging in Patients with Known or Suspected Coronary Artery Disease. 2006-present.
- Principal Investigator at Montefiore Medical Center for: Post-Revascularization CardIac PET/CT Imaging Correlation Study (PRECIPICE). 2006-present.
My group is interested in targeted radionuclide therapy of cancer and infectious diseases. Radionuclides are radioactive atoms which emit particles capable of destroying the cells extremely efficiently. Even such simple molecule as glucose when “armed” with positron-emitting radionuclide -18-Fluorine can become effective in killing cancer cells. Monoclonal antibodies are perfect “vehicles” for targeted delivery of radionuclides to the cancerous or microbial cells. Such therapeutic modality is called radioimmunotherapy. In our work we are trying to answer the following questions:
Can radiolabeled organism-specific antibodies be effective in killing microbial cells and what are the radiobiological and immune mechanisms of this killing? This project is a collaborative venture with Dr. A. Casadevall's Laboratory and the model organism for developing radioimmunotherapy of infection is Cryptococcus neoformans. Monoclonal antibodies developed in Casadevall's Lab which bind to C. neoformans capsule are labeled with radionuclides emitting alpha- or beta-particles such as 213-Bismuth and 188-Rhenium and interaction of these labeled mAbs with C. neoformans cells is studied in vitro and in vivo. We have also expanded this approach to treatment of bacterial infection (S. pneumoniae) in collaboration with Dr. L. Pirofski and of HIV-1 in collaboration Dr. H. Goldstein and Dr. S. Zolla-Pazner (NYU).
Can melanin being an intracellular antigen serve as target in radioimmunotherapy of metastatic melanoma? This project is also being carried out in collaboration with Dr. A. Casadevall who developed the fungal melanin-binding mAb and came up with the idea to use it as vehicle for radionuclides for radioimmunotherapy of melanoma. We utilize xenografted models of human melanoma with different degrees of pigmentation in nude mice for efficacy and toxicity studies. The project is in advanced pre-clinical stage. We are also investigating the use of fungal and human melanin-binding peptides as alternative carriers of radionuclides to the melanoma cells.
Can high doses of positrons (anti-particles for electrons) delivered by standard Positron Emission Tomography agent 18-Fluorine-labeled glucose (FDG) be therapeutic in metastatic metabolically active cancers? In collaboration with Drs. M. Charron and J. Pollard we demonstrated the possibility of using high dose FDG in animal models of breast cancer by measuring levels of apoptosis/necrosis in treated tumors, evaluating efficacy and toxicity of treatment in breast tumor-bearing animals, and establishing correlation of FDG uptake in the tumors with the levels of glucose transporters (GLUTs). We are planning to apply this approach to treatment of other metabolically active cancers such as lung and pancreatic cancers for which therapeutic options are very limited.
Our research focused on discovery and development of new therapeutic, diagnostic agents and new biomarkers for cancer, cardiovascular, Central Nervous System disorder and diabetes diseases. Our research is interdisciplinaryn nature and is the union between chemistry, biology and molecular imaging, biomolecular nanotechnology and molecular modeling. We are working in these interdisciplinary areas Organic Synthesis/ Radiochemistry; Chemical Biology; Molecular Imaging; and Biomolecular Nanotechnology.
Discovery and development of new reactions (using organocatalyst and Boron catalyst), and application of new reactions to the synthesis of chemical libraries of diversity oriented small molecules.
Chemical Biology and Chemical Genomic
Using small molecules studying the biology of the diseases (studying the mechanism of signal transduction process).
Using micro-PET approach to diagnose the diseases at early stage.
Developing new imaging agents (for known target); Developing new targeting agents (new Biomarker).
Development of RGD Peptidomimetic libraries for Glioblastoma Multiforme.
Malignant gliomas, the most common primary brain tumors, remain largely incurable despite intensive multimodality treatment including surgical resection, irradiations, and chemotherapy. Several investigators have shown a correlation between the expression of avβ3 and the metastatic potential of Glioblastomas. It has also shown that the avβ3 integrin is also important during tumor-induced angiogenesis (proliferation of blood vessels). The involved endothelial cells (inner lining of the new blood vessels) express avβ3 to adhere on the extra cellular matrix during migration towards the tumor. The development of radiolabeld avβ3 antagonists, in the combination with PET, should allow targeting of avβ3 positive tumors (tumor cells or involved cells) and an in vivo quantification of the receptor density and thus provide a helpful tool for treatment planning. We are synthesizing small organic Azabicyclo [x.3.0] alkane aminoacids as Pseudopeptide attaching with RGD peptidomimetics (peptidemimic bond is more stable to proteolysis). We will also radiolabel these compounds with a PET (Positron Emission Tomography) isotope (F-18 and I-124) to find out the bio-distribution of these molecules in vivo using an animal PET scanner (micro PET). The radiolabeled new compound could potentially be useful as an imaging agent for early diagnosis of GBMs (which is not currently available) non-invasively. We also plan to label one of these compounds with
I-131 for potential use as radio-molecular therapeutic agent. We hope that these studies will lead to development of effective therapeutics and diagnostics for glioma tumors and other avβ3 integrins.
Nanoparticle libraries for rhabdoid tumor imaging and therapeutics.
Rhabdoid Tumors has a very grim prognosis due to its unresponsiveness to the conventional chemotherapeutic agents. Studies from Dr. Kalpana’s laboratory has demonstrated that pharmacological intervention with N- (4-hydroxyphenyl) retinamide is effective in down modulating cyclin D1, inducing G1 arrest and apoptosis in rhabdoid cell lines in vitro and tumor growth inhibition of RTs in xenograft models in vivo. Though this molecule is very promising there are few constrains to use this molecule in human. The molar concentration required in achieving the desired cytocidal effect with 4-HPR alone in mice might not be obtainable in human and this molecule does not pass through the blood brain barrier freely. Therefore, treating RTs of the brain may not be possible. In this study we hypothesize that, by structural modification/manipulation of this molecule and by linking with nonoparticle, not only increase its potency but also it will cross the blood brain barrier freely. We hope that the new compound will not only physically reach the brain tumors through the blood brain barrier, but also will be more potent than the current compound i.e., 4-HPR and will show significant tumorocidal effect on RTs. We will also radiolabel this compound with a PET (positron emission tomography) isotope (F-18 and I-124) to find out the bio-distribution of this molecule in vivo using an animal PET scanner (micro PET). The radio-labeled new compound could potentially be useful as an imaging agent for early diagnosis of RTs (which is not currently available) non-invasively. We also plan to label this compound with I-131 for potential use as radio-molecular therapeutic agent.
Use of biolomolecules in nanotechnology (synthesize nanoscale biological molecules to study the structure activity relationship of the compounds)
Nanobiology: Use of nanotechnolgy for early diagnosis of diseases using micro-PET.
Clinical value of pet-ct in squamous cell carcinoma of the head and neck
The project is being carried out in collaboration with Dr. Richard V. Smith and the Department of Otolaryngology, Montefiore Medical Center. We are assessing the staging accuracy of PET alone, PET-CT utilizing low-dose CT and diagnostic CT with IV contrast or MRI. This will be compared with finding at surgery, and the imaging result effects on clinical management will be measured.
Sodium/iodide symporter (nsi) and radioiodide therapy in metastatic breast cancer
The project is being carried out in collaboration with the Department of Oncology, Montefiore Medical Center, and the Departments of Epidemiology and Population Health and Molecular Pharmacology, Albert Einstein College of Medicine. The data for this study has been collected and is currently being analyzed. NIS is present in breast cancer specimens of patients with metastatic breast cancer and appears functional. We are examining the survival differences in patients with NIS positive and negative disease. Radioiodide therapy with thyroid suppression is safe in patients with refractory metastatic breast cancer, but further exploration is necessary to evaluate the dosimetry and efficacy of this therapy.
Principal Investigator for Multicenter Trial (involving Montefiore Medical Center, Weill-Cornell and Mt. Sinai School of Medicine) entitled: The Incremental Value of Attenuation Correction on the Diagnostic Accuracy of Stress Radionuclide Myocardial Perfusion Imaging (IVAC). 2002-ongoing.
While the high diagnostic and prognostic utility of stress radionculide myocardial perfusion imaging is well established, the frequent presence of image artifacts can significantly reduce the accuracy of image interpretation. A large proportion of these artifacts are the result of nonuniform image attenuation, Compton scatter, and depth dependent reduction of spatial resolution. These problems contribute to excess referrals to coronary angiography. Recently, hardware and software systems have been developed to compensate for these artifacts, and are now sold as options with most commercial imaging systems. A few published studies have shown benefit from these attenuation correction systems, but others have not. As a result of conflicting reports, many physicians are unsure whether attenuation correction should be used. It is unclear whether attenuation correction is useful to experienced readers, to less experienced readers, both, or neither. Therefore, the purpose of this study is to look, in a systematic way, at the incremental diagnostic accuracy, if any, of incorporating attenuation correction into perfusion image interpretation when used by readers of varying experience. We will specifically evaluate the "Vantage Pro "attenuation/scatter/resolution recovery system that is sold with Philips/ADAC imaging systems. We will identify consecutive patients who underwent stress myocardial perfusion imaging with Vantage Pro attenuation correction (AC) and who had cardiac catheterization within 3 months at Montefiore Medical Center (Moses Division only), Mt. Sinai, and NYPH Weill Cornell (all sites have Philips/ADAC Vantage Pro systems). Based on statistical considerations, we will identify a total of 200 patients (total from all sites combined). We will also identify 50 patients (total from all sites) who had a <=5% pretest likelihood of CAD (controls). Raw images will be retrieved from storage media and processed both with and without AC applied. A total of 3 to 4 experienced and 4 less experienced readers (fellows) will interpret AC and non AC images individually. A subset of images will also be interpreted by consensus. Image interpretation results will be correlated with results from cardiac catheterization to determine if AC adds incremental diagnostic accuracy.
Principal Investigator at Montefiore Medical Center for multicenter trial: A Phase III, Randomized, Double-Blind Study of Intravenous CVT-3146 vs. Adenoscan in Patients Undergoing Stress Myocardial Perfusion Imaging. Sponsor: CV Therapeutics, Inc. 2003-2005.
A large percentage of patients referred for stress radionculide myocardial perfusion imaging are unable to exercise to a satisfactory heart rate workload, and therefore need to undergo pharmacologic stress testing. While pharamcoligc stress agents, such as the commonly used adenosine, provide high diagnostic accuracy, they cause frequently bothersome, and sometimes potentially harmful side-effects during stress testing. Adenosine works by interacting with receptors that cause coronary vasodilation, but unfortunately adenosine also cross-reacts with other receptors causing such problems as heart block and bronchospasm. To address this problem, pharmacologic agents are being devloped that will be more specific for the desired stress effect, and will less likely affect receptors that cause side-effects. One of these agents is CVT-3146, to be called Regadenoson, a selective pharmacologic stress agent that also has the advantage of convenient bolus administration (as opposed to infusion). At Montefiore Medical Center we participated in a multicenter trial looking both at the safety of Regadenoson during stress testing, and comparing perfusion image quality of patients undergoing both adenosine and Regadenoson stress testing.
Principal Investigator at Montefiore Medical Center for: An open-label, multicentre, phase 3 study evaluating the prognostic usefulness of I123-mIBG scintigraphy for identifying subjects with heart failure who will experience an adverse cardiac event. 2005-ongoing.
Congestive heart failure is becoming an epidemic in the developed world, affecting 5 million people in the USA, with a 50% 5 year-death rate. Our understanding of heart failure has recently improved in that we now understand the importance of neurohormonal factors in worsening the patient’s condition, and how therapeutically addressing these neurohormonal factors can improve patient outcome. In particular disruption of normal cardiac autonomic innervation plays an important role in the pathophysiology of heart failure. The radiotracer 123I-MIBG (metaiodobenzylguandine) can image sympathetic innervation of the heart, and previous studies have shown that cardiac MIBG imaging can assess a patient’s condition and prognosis, as well as help guide medical management including pharmacologic therapy and perhaps the potential benefit of mechanical devices such as an implantable cardiac defibrillator (ICD). At Montefiore Medical Center, the Division of Nuclear Medicine, with the assistance of the Division of Cardiology, is partiicpating in a multicenter international Phase III trial investigaitng the clinical utility of 123I-MIBG imaigng in patients wit Class II-III heart failure with ejection fraction < 35%. The study will correlate MIBG image findings with worsening prognsois, including clinical heart failure worsening, the development of potentially life threatening arrhythmia, and cardiac death to determine definitively how MIBG imaging can help improve the outcome of patients with congestive heart failure.
Co-investigator: Comparison of 64-slice multidetector coronary CT angiography with stress SPECT Radionuclide Myocardial Perfusion Imaging in Patients with Known or Suspected Coronary Artery Disease. 2006-present.
Recent developments promise to revolutionize cardiac imaging. One exciting innovation is the multislice CT. These multidetector machines allow imaging with sufficient spatial and temporal resolution to image small, moving coronary arteries, with the potential to noninvasively diagnosis coronary artery disease during an approximately 15 second patient imaging procedure. The goal is to better identify patients with coronary disease who could benefit from aggressive therapy before a catastrophic cardiac event, and also to determine which patients with disease do not need aggressive, invasive intervention. Nevertheless, at the present time CT coronary angiography (CTA) looks only at cornary anatomy and cannot portray the physiologic signfiicance of coronary lesions detected. Stress radionuclide perfusion imaging, on the other hand, is a well established techique for assessing the physiologic signficiance of coronary disease, thereby serving as a strong perdictor of patient prognosis and recently shown to be a powerful tool to direct patient management. Many expect that CTA and stress radionuclide myocardial perfusion imaging will be complementary in providing information to help manage patients with known or suspected coronary artery disease. This research study, performed jointly by the Department of Radiology and the Division of Nuclear Medicine, will compare findings on CTA and stress perfusion imaging in an inner city population of outpatients referred for nuclear testing.
Principal Investigator at Montefiore Medical Center for: Post-Revascularization CardIac PET/CT Imaging Correlation Study (PRECIPICE). 2006-present.
Coronary revascularization is commonly performed to treat coronary artery disease. While patients generally improve after revascularization, recurrent signs and symptoms are common. Although current non-invasive imaging modalities often help determine the cause of recurrent symptoms, in many cases this is not so. In particular, if a patient has recurrent symptoms, it can be difficult to distinguish among occurrence of disease in the vessel used for revascualrization, progression of disease in the native coronary vessels, or if the problem is of a non-cardiac etiology. Therefore an improved noninvasive imaging modality for such patients would be clinically beneficial. Recently developed noninvasive hybrid imaging techniques, such as cardiac PET/CT, have potential value in this clinical situation. With regard to radionuclide coronary perfusion imaging, PET has been shown to have a mildly better diagnostic accuracy than more routinely used SPECT imaging. Hybrid systems that allow one to perform attenuation correction with CT transmission maps promise even greater accuracy. Finally, the hybird technology allows one to look not only at coronary anatomy with CT angiography (CTA), but also to superimpose the coronary arteries on the PET perfusion images. By this one sees simultaneous images of coronary anatomy and physiology, allowing better assessment of potentially complex anatomy, thereby promising improved management of these patient. In the proposed study, patients with a previous CABG or PCI who are being referred for invasive coronary angiography to determine the etiology of recurrent signs or symptoms will be offered to first undergo a noninvasive combined stress Rb-82 PET perfusion and CT coronary angiogram with calcium scoring. The ability of Rb-PET to identify the presence and location of CAD will be compared with the combination of PET and CTA in terms of the ability to predict findings on subsequent invasive coronary angiography. The hypothesis is that the CTA will add incremental diagnostic accuracy to Rb-PET alone. The study will also look at the potential value of a coronary calcium score. Finally, image data will be correlated with patient prognosis.