Most patients with solid tumors die of tumor recurrence at the same site or metastasis of the tumor to distal sites. An intermediate step in both recurrence and metastasis is a stage called tumor dormancy, where the cancer cells are suppressed by a normal extracellular matrix (ECM) and by other mechanisms. Such cells can appear histopathologically normal and therefore escape detection. Like metastases and recurrent tumors, dormant cells are resistant to traditional therapeutics. Breast cancer, in particularly triple negative breast cancer (TNBC) and basal like breast cancer (BLBC), are poorly differentiated, highly aggressive (recurrent/metastatic), refractory to treatment and dormant tumor cells have been found years after remission in BC patients. Sometimes, these suppressed cells will reactivate and begin actively growing, forming either a metastasis or a local recurrence. DormaTarg, Inc. has developed a novel drug testing platform to model suppression by the normal ECM (U.S. Patent 7,575,926). We have used this model to screen chemical libraries for compounds capable of preferentially killing dormant cancer cells in an effort to target metastasis and recurrence at a previously unexploited point, the dormant or suppressed tumor micrometastasis. In our first screen of 2,300 compounds, three lead compounds were identified, designated DT-310, DT- 320 and DT-330. In the phase I portion of this SBIR proposal, these compounds were evaluated in an in vivo model of tumor dormancy (Patent Pending) and in an established metastatic orthotopic basal- like breast cancer (BLBC) model. It was found that one compound, DT-320, had superior antitumor efficacy and low toxicity in these models as compared to standard agents doxorubicin (DOX) and gemcitabine (GEM). The goal of the studies in this phase II application is to complete pre-good laboratory practices (pre-GLP) evaluation of DT-320 to support DormaTarg, Inc. moving forward with an IND from the FDA for this first in class therapeutic.
Aim 1 is to determine the odse escalation, scheduling and reversibility of the antitumor effect of DT-320 in vivo.
Aim 2 is to extend the anticancer efficacy of DT- 320 in breast tumors in vivo.
Aim 3 evaluates the pharmacokinetic parameters of DT-320 in vivo.
Aim 4 characterizes of mechanism of DT-320 tumor kill.
Triple negative breast cancer (TNBC) and basal like breast cancer (BLBC) are often highly aggressive (recurrent/metastatic). While there are several therapies available for TNBC/BLBC, survival rates for these cancers remain low. This project tests a novel approach to treating TNBC/BLBC, attacking dormant tumors.
|Hurst, Robert E; Bastian, Anja; Bailey-Downs, Lora et al. (2016) Targeting dormant micrometastases: rationale, evidence to date and clinical implications. Ther Adv Med Oncol 8:126-37|
|Hurst, Robert E; Hauser, Paul J; You, Youngjae et al. (2015) Identification of novel drugs to target dormant micrometastases. BMC Cancer 15:404|
|Bailey-Downs, Lora C; Thorpe, Jessica E; Disch, Bryan C et al. (2014) Development and characterization of a preclinical model of breast cancer lung micrometastatic to macrometastatic progression. PLoS One 9:e98624|
|Hurst, Robert E; Hauser, Paul J; Kyker, Kimberly D et al. (2013) Suppression and activation of the malignant phenotype by extracellular matrix in xenograft models of bladder cancer: a model for tumor cell ""dormancy"". PLoS One 8:e64181|