• EMCIT technology
  
• Cancer detection blood assay

Dr. Kassis’ translational studies are extremely compatible with industry efforts to develop improved radiopharmaceuticals for the noninvasive detection (imaging) and therapy (ß- and alpha-particle emitting radionuclides) of cancer, and sensitive tests for the detection of genomic and proteomic cancer signatures in blood and other bodily fluids. Dr. Kassis generated the paradigm-shifting EMCIT prodrug approach based on his years of studying radioisotopes, and his keen understanding and expertise in dosimetry, radioactive decay emission in low and high energy particle emitters, radiobiologic mechanisms, in silico modeling, organic chemical synthesis, radiolabeling, bioinformatics, data mining, and cancer biology. EMCIT is unique because it combines targeting and entrapment of selective, radiolabeled, small molecules within the extracellular milieu of cancer tissues with a radioactive, cross-fire capability. The targeting and entrapment are based on a catalytic activation mechanism(s).

EMCIT allows for both intratumoral, intracompartmental, and systemic administration, and should be applicable to a broad range of primary and metastatic tumor lesions. By overriding cancer cell defense mechanisms, such as genetic heterogeneity, mutability, multidrug resistance, and biological barriers that severely hinder the efficacy of most other cancer treatments, the prodrugs employed in EMCIT offer significant advantages in two general areas. The first area is radioimaging, which would encompass diagnosis, pinpointing the location of cancers, and treatment response monitoring. The second area is cancer therapy, which is consequent to the targeting of all primary or metastatic cancer mass that overexpresses extracellular hydrolases.

In a separate oncology-related endeavor, Dr. Kassis has developed an extremely practical clinical test for detecting occult tumors. The method – which reports cancer-specific genomic and proteomic signatures – is based on the detection of circulating tumor cells that have been shed from solid tumors into the blood and other bodily fluids. This method has tremendous potential as a screening test for the presence of occult cancer, as an adjunct for diagnosis, and as a means of monitoring the patient’s response to therapy and disease progression. Similar to the EMCIT methodology, the commercial potential of this testing protocol is huge.

• Dr. Kassis is continuing his research into radioisotope dosimetry, decay, and the effects of this decay on biological macromolecules and cells. He is also investing significant resources toward his novel EMCIT prodrug approach for imaging and eradication of tumors and the development of a new blood assay that is highly effective in the early detection of primary and metastatic solid tumors.
• The EMCIT technology relies on tumor-mediated in situ conversion of water soluble radioactive low molecular weight prodrug molecules into water-insoluble molecules within the extracellular milieu of solid tumors and metastatic lesions. The localization and accumulation of the radioisotope within sites of tumor growth enables the destruction of surrounding tumor tissue while sparing normal tissues and/or the radioimaging (SPECT/PET) of tumors before or after other therapeutic intervention. The scientific community recently recognized the inventive principle of EMCIT, as it was featured on the cover of a recent issue of the prestigious Cancer Research.
• EMCIT exploits the robust expression and secretion into the extracellular space of degradative hydrolases by solid tumors. The negatively charged, prodrug molecules, for example radioiodinated with either ¹³¹I for cytotoxicity or ¹²³I for radioimaging, are designed to be incapable of traversing cell membranes. However, once within the extracellular space of solid tumors, they are converted to water-insoluble precipitates by hydrolases present in high concentrations within the extracellular fluid surrounding tumor cells (but exist at much reduced concentrations in blood and normal tissues). The entrapment of the radiolabeled aggregate causes local cell killing that cannot be counteracted by drug resistance mechanisms or loss of radiolabel due to diffusion.
• Dr. Kassis also developed a highly sensitive simple blood (and other bodily fluid) assay for early diagnosis of cancer. This genomic/proteomic test reports the presence of occult tumors (screening and detection of recurring disease) and identifies what type it is. Since there is a significant medical need for an inexpensive, non-invasive, highly specific and sensitive cancer detection system that can be easily performed in clinical laboratories, the assay holds great promise for improving the early diagnosis of cancer and enables a rapid assessment of patient response to therapy.

Dr. Kassis' innovative technology for detecting circulating cancer cells was highlighted in a recent interview with Harvard Science. The interview can be accessed at: http://harvardscience.harvard.edu/medicine-health/articles/hms-professor-devises-single-test-cancers-0

Dr. Kassis is the Director of the Radiobiology and Experimental Radionuclide Section within the Department of Radiology. He is a renowned world expert on the physics, chemistry, biochemistry, and therapeutic uses of radionuclides. He has extensive experience in radiolabeling of molecules, biologicals, dosimetry, radiobiological effects, and cancer imaging and therapy using radiolabeled molecules and prodrugs. Professor Kassis has also held various important positions including the directorship of the Laboratory for Radionuclide Gynecologic Oncology at the Dana-Farber Cancer Institute, the chairmanship of the Task Force on Dosimetry of Radiolabeled Antibodies within the Medical Internal Radiation Dose (MIRD) Committee, and the presidency of the American Board of Science in Nuclear Medicine. He has supervised over 60 postdoctoral fellows and has published nearly 180 peer-reviewed articles, 30 book chapters/reviews, and holds 34 US and world patents.

Dr. Kassis’ lab reported recently that Auger electrons emitted from ¹²⁵I induces double-strand breaks (DSBs) in circular DNA. The magnitude of the effects were dependent on the DNA form, that is, supercoiled or relaxed. DSBs in supercoiled DNA, could be attributed solely to Auger electrons while DSBs accumulating in relaxed DNA were also generated by ¹²⁵I-dependent hydroxyl radical formation. Moreover, Auger electrons emitted by DNA-incorporated ¹²⁵I can induce apoptosis in a dose-dependent manner and correlates with cell radiosensitivity. In a related study, the lab was able to localize ¹²⁵I specifically to the nucleus by radioiodinating Hoechst 33342, a DNA binding dye. Radioactive decay derived from the nuclear accumulation of ¹²⁵I-Hoechst 33342 caused DSBs and a concomitant increase in cell death.

Dr. Kassis has also made important contributions to radiolabeling methodology. His approach of including DMSO in reaction mixtures significantly improved the yield of radioiodination reactions. This simplified, high yield radioiodination method is now widely used by other labs.
 

Biological Mechanisms and Pathways

• Apoptosis •
• Bioinformatics •
• Extracellular hydrolases •
• Oncology
•  

Cancer

• Apoptosis •
• Cancer •
• Oncology
•  

Diagnostics

• Circulating tumor cell
•  

Disease Mechanisms

• Cancer
•  

Research Tools and Instrumentation

• Bioinformatics •
• Cross-fire irradiation •
• Data mining •
• In silico molecular modeling •
• Mouse tumor models •
• Radioiodination •
• Radionuclide
•  

Therapeutic Discovery Tools and Assays

• Cancer •
• Data mining •
• In silico molecular modeling •
• Non-invasive therapy •
• Pharmacokinetics •
• Radiotherapy
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Therapeutics

• Cancer diagnostics •
• Cancer gene signature •
• Circulating tumor cell •
• Non-invasive detection •
• Prodrug •
• Radioimaging •
• Small molecule chemistry •
• Small molecule therapy
•