Cancer therapy efficacy is often limited by toxicity in normal tissues. The ability to target chemotherapy to cancer cells, largely bypassing normal tissues, would fundamentally improve the efficacy of cancer treatment. We recently showed that a scorpion-derived peptide, chlorotoxin, targeted the near infrared fluorescent molecule, Cy5.5 to cancer cells. This new molecular imaging conjugate permitted sensitive detection of cancerous foci as small as 200 cells. Unlike most targeting agents, CTX appears to target many types of solid tumors rather than one particular type. Whereas our previous work showed that CTX:Cy5.5 is a sensitive diagnostic agent, the current proposal seeks to determine whether CTX conjugates can be used as selective therapeutic agents. The broad, long-term goal of this research is to learn how to safely use CTX to deliver cytotoxic drugs to cancer cells, thus lessening chemotherapy side effects.
The specific aims of this proposal are to 1) identify the molecular target of CTX;2) identify normal tissues that bind CTX and define CTX binding heterogeneity in selected cancers;and 3) establish the efficacy and toxicity of CTX conjugated to a potent cytotoxic drug using mouse cancer models. The significance of this work is that CTX targeting has the potential to markedly increase the therapeutic index of conjugated chemotherapy. For cancer patients, delivering higher doses of therapeutics to cancer cells while sparing most normal tissues, could result in improved survival and quality of life.
The relevance of the proposed work is that chlorotoxin appears to be a molecule that has high potential to specifically deliver cancer therapies to cancer cells, largely bypassing normal tissues. For cancer patients, this means more therapy could be delivered to cancer cells while the patient experiences fewer side effects. Of particular interest is that chlorotoxin appears to bind to most types of malignant solid tumors rather than just one or two types.
|Correnti, Colin E; Gewe, Mesfin M; Mehlin, Christopher et al. (2018) Screening, large-scale production and structure-based classification of cystine-dense peptides. Nat Struct Mol Biol 25:270-278|
|Pei, Yanxin; Liu, Kun-Wei; Wang, Jun et al. (2016) HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. Cancer Cell 29:311-323|
|Rosenthal, Eben L; Warram, Jason M; de Boer, Esther et al. (2016) Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report. J Nucl Med 57:144-50|
|Fidel, Janean; Kennedy, Katie C; Dernell, William S et al. (2015) Preclinical Validation of the Utility of BLZ-100 in Providing Fluorescence Contrast for Imaging Spontaneous Solid Tumors. Cancer Res 75:4283-91|
|Parrish-Novak, Julia; Holland, Eric C; Olson, James M (2015) Image-Guided Tumor Resection. Cancer J 21:206-12|
|Girard, Emily; Ditzler, Sally; Lee, Donghoon et al. (2015) Efficacy of cabazitaxel in mouse models of pediatric brain tumors. Neuro Oncol 17:107-15|
|Hubert, Christopher G; Bradley, Robert K; Ding, Yu et al. (2013) Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. Genes Dev 27:1032-45|
|Akcan, Muharrem; Stroud, Mark R; Hansen, Stacey J et al. (2013) Correction to Chemical Re-engineering of Chlorotoxin Improves Bioconjugation Properties for Tumor Imaging and Targeted Therapy. J Med Chem 56:9807|
|(2013) Correction to Chemical Re-engineering of Chlorotoxin Improves Bioconjugation Properties for Tumor Imaging and Targeted Therapy. J Med Chem 56:9807|
|Lee, Michelle J; Hatton, Beryl A; Villavicencio, Elisabeth H et al. (2012) Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc Natl Acad Sci U S A 109:7859-64|
Showing the most recent 10 out of 16 publications