In vivo results

Stage II/III Metastatic Triple-Negative Breast Cancer, Mouse Model

We have developed a new therapeutic approach that relies on specific eradication of metastatic tumor cells through pharmacological inhibition of microRNA-10b. microRNA-10b is a master regulator of the viability of metastatic tumor cells and has been thoroughly validated as a promising therapeutic target in over 120 clinical studies across 18 metastatic cancer types.

The approach relies on a therapeutic agent that specifically inhibits microRNA-10b in metastatic cells. The therapeutic (TTX-MC138) consists of ultrasmall dextran-coated iron oxide nanoparticles, conjugated to antagomirs targeting microRNA-10b.

We demonstrated that TTX-MC138 could elicit durable regression of lymph node metastases in a mouse model of breast cancer with no evidence of systemic toxicity. Specifically, just four weekly treatments with TTX-MC138 in combination with low dose chemotherapy led to elimination of detectable lymph node metastases in all of the animals. Following elimination of metastases, therapy was discontinued. No recurrence of lymph node metastases was observed for the natural life of the animals and no mortality from cancer was evident for the duration of the study (See Figure Below).

Cancer Survival

Cancer survivor - stage 2

TTX-MC138 superior to control + low-dose doxorubicin*
Eliminates pre-existing local metastases

NT – No therapy | C – Control (Irrelevant oligo) | T – TTX-MC138 | dox – low-dose doxorubicin
Yoo, B. et al. Combining miR10b-targeted nanotherapy with low-dose doxorubicin elicits durable regressions of metastatic breast cancer. Cancer Res 75, 4407–4415 (2015).

Stage IV Metastatic Triple-Negative Breast Cancer, Mouse Model

We applied TTX-MC138 in a model of Stage IV breast cancer. We found that TTX-MC138 is taken up avidly by metastatic tumor cells in the lymph nodes, lungs, bone, and brain, following intravenous injection. Four to six weekly treatments in combination with low-dose chemotherapy were sufficient to cause durable regression of pre-existing distant metastases in 65% of the animals and inhibition of multiple organ metastases in 94% of the animals. As a result, cancer survival was dramatically improved (See Figure Below)

Cancer Survival

Cancer survivor - stage 4

TTX-MC138 superior to control + low-dose doxorubicin*
Eliminates pre-existing distant metastases

NT – No therapy | C – Control (Irrelevant oligo) | T – TTX-MC138 | dox – low-dose doxorubicin
Yoo, B. et al. Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer. Sci. Rep. 7, 45060; doi: 10.1038/srep45060 (2017).

*Doxorubicin was used to slow down cell division in tumor cells. In pre-clinical studies that utilize aggressive metastatic tumor models, the use of doxorubicin was necessary to allow TTX-MC138 to fully inhibit microRNA-10b. Because metastatic growth is slower in humans, the use of a cytostatic such as doxorubicin will likely be unnecessary, and TTX-MC138 would be administered as a monotherapy.

In vitro results

Based on the prior knowledge about the broad influence of microRNA-10b on a number of human malignancies, we embarked on a systematic investigation of its global effect on cancer. Our approach is based on our discovery that in addition to influencing invasion and migration of tumor cells, microRNA- 10b is responsible for the survival of metastatic cells. For that reason, we focused on investigation of tumor cell viability following microRNA-10b inhibition using TTX-MC138 in a panel of representative cell lines including metastatic and non-metastatic cancers.

The sensitivity to TTX-MC138 was tested in 624 human cell lines representing the spectrum of metastatic and non-metastatic cancers. TTX-MC138 demonstrated therapeutic efficacy in 77% of the human tumor cell lines tested. This is consistent with a very high specificity of the effect and proves sensitivity to TTX-MC138 in multiple cancer types.

PLOS ONE | July 2018