Early stage ovarian cancer is typically asymptomatic. Undiagnosed until the disease has reached an advanced stage, the disease presents extensive intra-abdominal peritoneal metastases. Standard of care treatment includes either a surgical cytoreduction to remove tumor bulk, then platinum-based chemotherapy or primary neoadjuvant chemotherapy followed by interval cytoreduction after tumor shrinkage. Despite successful initial treatments, 80-90% of women with advanced cancer experience tumor recurrence. Surgical outcomes can vary considerably since some cancerous lesions are not visible to naked-eye surveillance or palpation, the only tools available to the surgeon in real-time. There is significant evidence that an extended disease-free period or even a cure are causally related to how much cancerous tissue is excised. A sensitive, specific, easy to visualize dye which precisely highlights small (< 5mm) and otherwise hidden lesions would better differentiate healthy from cancerous tissue, enable better informed surgical decisions and lead to better outcomes for ovarian cancer patients. In this collaboration between Molecular Targeting Technologies, Inc. and Weill Cornell Medical School we are developing a novel, tumor-specific agent for intraoperative near-infrared fluorescence imaging to guide ovarian cancer surgeries in real-time. In preliminary feasibility studies we have identified an optimized pH-sensitive near-infrared fluorogenic dye (CypH-11) which is non-fluorescent in normal tissues, but fluoresces immediately when sprayed onto cancer tissue, whose microenvironment is slightly acidic. We hypothesize that the cancer selective staining by CypH-11 will make the surgical debulking procedure precise and effective by locating normally unseen small and occult lesions, achieving a better surgical outcome. This approach could herald a paradigm shift in surgical oncology. In direct to Phase II SBIR studies we will scale-up synthesis and manufacture of CypH-11 and the final formulated vial in compliance with cGMP; perform preclinical optimization and validation of the CypH-11 formulation in a subcutaneous murine model and validate its sensitivity and specificity in an orthotopic model that simulates the clinical setting; and obtain pharmacokinetic, biodistribution and toxicity data to support an exploratory IND filing. The application will be submitted to the FDA anticipating a Phase 0 first-in-human study.
Public Health Relevance Statement: There is no reliable way for surgeons to see all cancerous tissue, including small lesions, in real-time, while operating. We are developing a sprayable, fast-acting, sensitive and tumor specific fluorescent agent which makes ovarian cancer tumors glow under near infrared light during surgery. Our technology can potentially make the ovarian cancer debulking procedure more precise and safer, enabling the surgeon to see more cancerous tissue, improving surgical outcomes and reducing the odds of recurrence.
Project Terms: Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Biopsy; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Chemistry; Clinical Research; Clinical Study; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Dyes; Coloring Agents; Endoscopy; endoscopic imaging; Eye; Eyeball; Feasibility Studies; Female; Fluorescence; Fluorescent Dyes; Fluorescence Agents; Fluorescent Agents; fluorescent dye/probe; Freeze Drying; Freeze Dryings; Lyophilization; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Human; Modern Man; In Vitro; Lead; Pb element; heavy metal Pb; heavy metal lead; Light; Photoradiation; Methods; Mus; Mice; Mice Mammals; Murine; Metastasis; Metastasize; Metastatic Lesion; Metastatic Mass; Metastatic Neoplasm; Metastatic Tumor; Secondary Neoplasm; Secondary Tumor; cancer metastasis; tumor cell metastasis; Neoplasm Metastasis; Cancer Staging; Neoplasm Staging; Tumor Staging; Diagnostic Neoplasm Staging; Palpation; Patients; Pharmacokinetics; Drug Kinetics; Platinum Black; Pt element; Platinum; Common Rat Strains; Rat; Rats Mammals; Rattus; Recurrent; Recurrence; medical college; school of medicine; medical schools; Sensitivity and Specificity; Staining method; Stains; Technology; Time; Tissues; Body Tissues; Toxicology; Translating; Woman; base; Vial device; Vial; improved; Procedures; Solid; Clinical; Phase; Evaluation; Lesion; Visual; Relapsed Disease; Recurrent disease; Collaborations; Letters; Normal Tissue; Normal tissue morphology; tool; Debulking; cytoreductive surgery; surgical cytoreduction; tumor cytoreduction; Tumor Debulking; Serous; Peritoneal; intraperitoneal; subdermal; subcutaneous; Techniques; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; residual disease; Residual Tumors; Surgeon; experience; Induction Therapy; NEOADJ; Neoadjuvant; Neoadjuvant Treatment; Neoadjuvant Therapy; Toxicities; Toxic effect; novel; Female Reproductive Cancer; Gynecologic Cancer; Gynecological Cancer; Malignant Gynecologic Neoplasm; Malignant Gynecologic Tumor; Malignant Tumor of the Female Reproductive System; gynecologic malignancy; gynecological malignancy; Malignant Female Reproductive System Neoplasm; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; chemotherapeutic agent; Modeling; Advanced Cancer; Advanced Malignant Neoplasm; Meta-Analysis; cancer surgery; Second Look Surgery; Second Look; Surgical Revision; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; image-based method; imaging method; imaging modality; Dose; Bulky Disease; Data; Detection; Intra-abdominal; Molecular Target; Prior Chemotherapy Regimens; Prior Chemotherapy; oncologic surgery; Surgical Oncology; in vivo Model; Cancer Patient; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; Resected; Development; developmental; Image; imaging; pre-clinical; preclinical; Biodistribution; Outcome; scale up; Cancer cell line; human study; Cancerous; chemotherapy; mouse model; murine model; tumor; standard of care; personalized medicine; personalization of treatment; personalized therapy; personalized treatment; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; Near-infrared optical imaging; NIR imaging; NIR optical imaging; Near-infrared Fluorescence Imaging; near infrared imaging; image guided; image guidance; Formulation; improved outcome; surgery outcome; surgical outcome; first-in-human; first in man; real-time images; realtime image; prognostic indicator
