Ralph DaCosta

Research Synopsis

Translationally-Driven Molecular Imaging in Cancer and Other Diseases

Keywords: Molecular imaging, cancer diagnosis and treatment, nanotechnology, next- generation image-guided interventions, molecular probes, endoscopic oncology, intravital experimental models of cancer, intravital optical microscopy, radiobiology, tumor microenvironment, personalized cancer medicine, medical devices, clinical trials.

The DaCosta Lab is focused on the development and application of next-generation multimodal imaging and molecular probe technology platforms for: i) detecting disease early, ii) elucidating disease mechanisms, iii) monitoring treatment response early and iv) facilitating real-time image-guided interventions. Our goal is to accelerate the translation of these “bioimaging” capabilities into multiple clinical domains with the longer term vision of advancing the delivery of personalized (cancer) medicine, curing disease and improving quality of life for patients. Currently, the lab has two main areas of work:

I. Preclinical Cancer Biology Research

Radiation therapy is a mainline cancer treatment. Improving the response of solid tumors to radiation therapy (including in combination with emerging therapies) is clinically important. Using sophisticated intravital (optically-enabled) microscopy methods, small animal x-ray microirradiators and new experimental animal models of human cancers developed in our lab, we are investigating how tumors, their vasculature and microenvironment respond to radiation therapy in vivo ( Fig. 1 ). Specifically, we are interested in studying the effect of radiation (alone or in combination with other therapies) on tumor vasculature and hypoxia, understanding the influence of tumor vasculature and hypoxia on radiation response, and elucidating new treatment strategies to target these systems. We are also developing new multimodal microscopic imaging strategies to investigate the influence of radiation therapy on the tumor microenvironment (e.g. epithelial mesenchymal transition), tumor cell cycle, cancer-initiating cells and metastases, as well as to optimize the use of new (hypoxia-activated) drugs. Overall, this research is aimed at overcoming current cure-limiting biological barriers in radiation therapy and developing new treatment strategies informed by a better understanding of mechanisms of response in solid tumors. Our on-going work with collaborators has led to the development of a new class of oxygen-generating nanoparticles that can generate molecular oxygen within the tumor microenvironment to improve the effectiveness of radiation treatment in a clinically-relevant manner. This work has also led to the development of new intravital animal models of human cancers (e.g. pancreatic, breast, bone marrow, brain) for imaging-based investigations of other cancer systems, treatments, and technologies (e.g. leukemia, cancer stem cells, virotherapy, biomaterials, regenerative medicine).

II. Imaging Clinical Trials

The development of new imaging technologies to improve disease diagnosis, guide therapeutic interventions and monitor response to treatments enables optimal clinical outcomes for patients with cancer and other diseases. We have developed new first-in-class optically-based imaging platforms for intraoperative surgical guidance in (breast) cancer patients and point-of-care imaging of infectious diseases. The DaCosta Lab’s clinical trials group has developed a standardized system for conducting Phase 0-III clinical trials of medical devices and imaging agents under strict Good Clinical Practice policies in close collaboration with Health Canada, institutional regulatory bodies and industry partners. Our interest is to develop next generation imaging technologies that are rapidly translated to first-in-human studies with a longer term vision of commercializing the innovations for broader value to patients and health systems around the world. Currently, our certified clinical trials group is conducting two Phase I-II clinical trials with local and international partners to investigate: 1) intraoperative fluorescence image-guided margin assessment and surgical resection in advanced breast cancer ( Fig. 2 ) and 2) intraoperative fluorescence and photoacoustic imaging of breast and thyroid cancers. We are also conducting five Phase II trials investigating the use of point-of-care optical imaging technologies for detection of bacterial infection in wounds and cancer surgical sites.

Recent Publications

• Maeda A, Bu J, Chen J, Zheng G, DaCosta RS. Dual In Vivo Photoacoustic and Fluorescence Imaging of HER2 Expression in Breast Tumors for Diagnosis, Margin Assessment, and Surgical Guidance. Mol Imaging. 2014 Nov 1;13(0):1-9. PubMed PMID: 25430722.
• Li J, Cai P, Shalviri A, Henderson JT, He C, Foltz WD, Prasad P, Brodersen PM, Chen Y, DaCosta R, Rauth AM, Wu XY. A multifunctional polymeric nanotheranostic system delivers doxorubicin and imaging agents across the blood-brain barrier targeting brain metastases of breast cancer. ACS Nano. 2014 Oct 28;8(10):9925-40. doi: 10.1021/nn501069c. Epub 2014 Oct 13. PubMed PMID: 25307677.
• Wu YC, Kulbatski I, Medeiros PJ, Maeda A, Bu J, Xu L, Chen Y, DaCosta RS. Autofluorescence imaging device for real-time detection and tracking of pathogenic bacteria in a mouse skin wound model: preclinical feasibility studies. J Biomed Opt. 2014 Aug;19(8):085002. doi: 10.1117/1.JBO.19.8.085002. PubMed PMID: 25089944.
• Prasad P, Gordijo CR, Abbasi AZ, Maeda A, Ip A, Rauth AM, DaCosta RS, Wu XY. Multifunctional albumin-MnO₂ nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response. ACS Nano. 2014 Apr 22;8(4):3202-12. doi: 10.1021/nn405773r. Epub 2014 Apr 4. PubMed PMID: 24702320.
• Espino A, Cirocco M, Dacosta R, Marcon N. Advanced imaging technologies for the detection of dysplasia and early cancer in barrett esophagus. Clin Endosc. 2014 Jan;47(1):47-54. doi: 10.5946/ce.2014.47.1.47. Epub 2014 Jan 24. Review. PubMed PMID: 24570883; PubMed Central PMCID: PMC3928491.
• Ottolino-Perry K, Tang N, Head R, Ng C, Arulanandam R, Angarita FA, Acuna SA, Chen Y, Bell J, Dacosta RS, McCart JA. Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis. Int J Cancer. 2014 Feb 1;134(3):717-30. doi: 10.1002/ijc.28395. Epub 2013 Aug 29. PubMed PMID: 23893655.
• Burrell K, Agnihotri S, Leung M, Dacosta R, Hill R, Zadeh G. A novel high-resolution in vivo imaging technique to study the dynamic response of intracranial structures to tumor growth and therapeutics. J Vis Exp. 2013 Jun 16;(76):e50363. doi: 10.3791/50363. PubMed PMID: 23793043; PubMed Central PMCID: PMC3727480.

Graduate Students

Christopher Gibson
Timothy Samuel