Strategies that successfully target and destroy human cancers must recognize differences between normal and malignant tissues. In this regard, an abnormal vasculature is being increasingly recognized as a consistent feature of solid tumors and a potential point of attack. Malignant solid tumors are generally comprised of a hypoxic, often necrotic core and a viable rim. The core has a poor vascular supply and is therefore deficient in nutrients and oxygen. Therapeutic interventions to date have focused on the well-vascularized outer shell of the tumor, as these are most susceptible to chemotherapeutic agents and radiation. In contrast, few therapies, target the inner, hypoxic core, which can make up a major part of the tumor's mass. For this purpose, we have investigated the potential of using live anaerobic bacteria. In particular, we developed a strain, termed Clostridium novyi-NT(C. novyi-NT), that is a spore-forming Gram-positive anaerobe whose toxicity was attenuated by eliminating a bacteriophage that carried its systemic toxin gene. C. novyi-NT has undergone pre-clinical efficacy and toxicity evaluations in several animal models. C. novyi-NT spores delivered through a single intravenous dose to mice results in substantial tumor regressions in most animal models. Cure rates of 20-30% are common when spores are used alone in immunocompetent mice or rabbits. In nude mice bearing human tumor xenografts, complete regressions are generally observed, and cures are routinely obtained when the spores are administered with selected radiation and chemotherapeutic protocols. Toxicity studies demonstrated no clinical toxicity and minimal pathologic toxicity in healthy animals. While toxicity in tumor-bearing animals was evident in mice, it was manageable with hydration or antibiotics. In this R01 application, we propose a first-in-man phase I clinical trial of C. novyi-NT spores in treatment- refractory solid tumors. We plan to (1) optimize the production of clinical-grade (GMP) C. novyi-NT spores, (2) conduct the phase I clinical trial for safety and efficacy, (3) measure the antibody and systemic inflammatory response to C. novyi-NT in humans, and (4) develop assays to evaluate C. novyi-NT spore pharmacokinetics in humans. Relevance to Public Health: The studies described in this application will evaluate a novel therapeutic strategy in patients with solid tumor malignancies and provide a detailed understanding of the safety, pharmacology and efficacy of live anaerobic bacterial spores in cancer patients. ? ? ?
| Bettegowda, Chetan; Sausen, Mark; Leary, Rebecca J et al. (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24 |
| Roberts, Nicholas J; Zhang, Linping; Janku, Filip et al. (2014) Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med 6:249ra111 |
| Bozic, Ivana; Reiter, Johannes G; Allen, Benjamin et al. (2013) Evolutionary dynamics of cancer in response to targeted combination therapy. Elife 2:e00747 |
| Kinde, Isaac; Bettegowda, Chetan; Wang, Yuxuan et al. (2013) Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci Transl Med 5:167ra4 |
| Killela, Patrick J; Reitman, Zachary J; Jiao, Yuchen et al. (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 110:6021-6 |
| Jiao, Yuchen; Killela, Patrick J; Reitman, Zachary J et al. (2012) Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3:709-22 |
| Krick, Erika L; Sorenmo, Karin U; Rankin, Shelley C et al. (2012) Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors. Am J Vet Res 73:112-8 |
| Diaz Jr, Luis A; Williams, Richard T; Wu, Jian et al. (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486:537-40 |
| Roberts, Nicholas J; Zhou, Shibin; Diaz Jr, Luis A et al. (2011) Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget 2:739-51 |
| Velculescu, Victor E; Diaz Jr, Luis A (2011) Understanding the enemy. Sci Transl Med 3:98ps37 |
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