PHOTO-ACTIVE BACKBONE FOR PHOTODYNAMIC THERAPY AND IMAGING
Genady Kostenich , Mor Herman and Arie Orenstein , Sheba Medical Center, Israel
Diagnostic tool for Imaging – solid cancer applications
The American Cancer Society estimates that over 1 million new cases of cancer are diagnosed in the U.S. each year. One in three Americans will develop cancer at some time in their lifetime (over 85 million). More than
500,000 in the U.S. will die (more than 1500 a day), making it the second leading cause of death in the U.S.
Early detection of cancer is a key to reducing mortality, because it allows treating malignant tumors in the initial stages more efficiently. However, small tumors (<
2 mm) known to be pre-invasive are difficult to diagnose because of limitation in sensitivity and resolution of conventional imaging techniques such as X-ray, CT, ultrasound and magnetic resonance imaging (MRI).
There is a need for selective and specific contrast agents allowing increased sensitivity of imaging methods in detection of early-stage disease. Oncology therapeutics research has focused on developing compounds that selectively target neoplastic processes with the hope that such agents will inhibit cancer cells proliferation and spare normal cells.
Cancer targeting based on receptor-specific pathways for both diagnostic and therapeutic purposes is a novel and promising trend in oncology. This trend has permitted to develop molecules that make available tumor detection/treatment with high sensitivity and specificity.
In the past decade, there has been increasing evidence for variety of peptide receptors over-expressed in cancer cells in comparison to normal tissue. The best data has been provided for somatostatin receptors (SSTr) present in neuroendocrine tumors. Somatostatin is a small peptide, a natural hormone that regulates release of several physiologically important biomolecules. Somatostatin analogs are the first class of receptor binding peptides having gained routine clinical application in oncology for treatment and diagnostic of cancer.
The cost of cancer and its effects on the U.S. economy was more than $150 billion in 2002. For diagnostic purposes approximately 15 million endoscopic procedures are performed each year in the U.S.: 10 million gastrointestinal endoscopic procedures, 4.4 million colonoscopies, and 500,000 bronchoscopies. Similar numbers pertain to endoscopic procedures world wide. Such endoscopic procedures are limited in sensitivity and resolution, moreover they are not without inconvenience/risk to the patient nor are they inexpensive (about $3,000 per procedure in Europe). A noticeable improvement of the procedure specificity by using a tumor-targeted fluorescent drug will contribute markedly to early detection of small, pre-invasive tumors that can be efficiently treated before the tumor becomes systemic. This will reduce the incidence of radical surgical interventions or of expensive adjuvant treatments, such as radio- and
chemotherapy. For example, the cost of thoracic surgery, when the tumor is operable, is about $9,000, while multimodal treatment (chemo-radiotherapy) for advanced lung cancer (stages IIIB&IV) is $45,000 per patient. Additionally, early detection leads to improved survival with a saving of $12,000 per life year.
We have discovered a stable ligand that binds somatostatin receptors on cancer cells. This molecule was labeled with a fluorescent moiety demonstrated high binding specificity to somatostatin receptors on cancer cells - in vitro as well as on tumors models in animals. Selective tumor uptake compared to normal tissues was demonstrated in mouse xenograft models of human lung and colon carcinomas. After administration, the agent is removed from normal tissues, being retained in the tumors for at least 72 hours, thus providing significant tumor-to-normal tissue ratio. The labeled conjugate emits green fluorescence under illumination with blue light and can be easily detected by fluorescence imaging techniques.
We developed a family of molecules with specific affinity to somatostatin receptors for detection and treatment of cancer. This study will be based on the SSTr-targeted agent which was shown to have tumor targeting properties and may serve as a platform for future development of novel cancer diagnostic and therapeutic drugs.
We will focus on (A) synthesis of SSTr-specific agents; (B) characterization of chemical/physical properties of the agents for optimization of the detection methods; (C) in vitro testing using SSTr positive cell lines for determination of the spectrum of biological activity; (D) in vivo testing using suitable animal models.
ü A novel SSTr-targeted drug for detection of malignancies using optical methods
ü A novel SSTr-targeted drug for detection of malignancies using MRI
ü A novel SSTr-targeted drug for treatment of malignancies
ü Tumor detection based on SSTr-specific agent linked to a fluorescent or magnetic resonance imaging moiety.
ü Treatment of SSTr-positive malignancies using a SSTr-specific agent with anti-tumor propertie.
- The SSTr-specific fluorescent drug can be applied for early diagnosis of SSTr-positive types of cancer using endoscopic methods (e.g. bronchoscopy, gastroscopy, colonoscopy, colposcopy). A variety of tumors including brain, breast, thyroid and prostate cancer can be detected by SSTr-targeted MRI contrast agent. Tumors demonstrating high selectivity in accumulation of a SSTr-specific diagnostic agent in comparison with normal tissues can be treated using a SSTr-specific therapeutic drug.
- The backbone molecule can be attached to other imaging agent for in-vivo imaging using PET or MRI.
- The backbone molecule can be attached to therapeutic agents for low dose selective therapy