Posted April 19, 2023

Yibin Kang, Ph.D., Princeton University
Yongna Xing, Ph.D., University of Wisconsin–Madison

The majority of breast cancer deaths result from metastatic disease, making the need for effective therapeutics to treat metastatic breast cancer urgent.¹ Two important challenges associated with metastatic breast cancer are the development of therapeutic resistance and the ability of tumors to circumvent the body’s natural immune detection and elimination strategies. Drs. Yibin Kang and Yongna Xing previously demonstrated that metadherin (MTDH) plays a critical role in cancer progression and chemotherapy resistance by creating a protein complex with Staphylococcal nuclease domain containing 1 (SND1). MTDH was also found to be overexpressed in 30%-40% of breast cancer patients, and this has been linked to poor overall outcome and metastasis-free survival.^2,3 In a recent pair of publications in Nature Cancer, Drs. Kang and Xing identified novel small molecule compounds that suppress tumor growth and metastasis by targeting the MTDH-SND1 complex, and also identified the role of MTDH in suppressing T-cell-mediated immune responses to cancer cells.

Previous investigation of the structure of MTDH-SND1 complexes demonstrated unique binding pockets in SND1 that interact with conserved portions of the MTDH protein. When the conserved portions of the MTDH protein are mutated, MTDH-SND1 interactions are prevented, thereby eliminating the tumor-initiating effects normally mediated by MTDH.⁴ With support from a fiscal year 2015 Breast Cancer Research Program (BCRP) Breakthrough Award – Funding Level 2 – Partnering Principal Investigator Option, Drs. Kang and Xing utilized this previous research to identify small molecules that bind directly to the SND1 binding pockets necessary to mediate the formation of MTDH-SND1 complexes. The research team found that two compounds significantly block the interaction of MTDH and SND1, with the most potent compound, methyltriazolopyridinamine (C26-A6), inhibiting tumor growth and metastasis in an animal model of triple-negative breast cancer without evidence of toxicity. In animal models, combination treatment with C26-A6 and the chemotherapy drug paclitaxel resulted in a further reduction in primary tumor growth and metastasis compared to treatment with C26-A6 or paclitaxel alone. From these results, Drs. Kang and Xing conclude that inhibition of the formation of the MTDH-SND1 complex represents a promising novel therapeutic target for metastatic breast cancer.

Dr. Kang’s team went on to further investigate the mechanisms underlying the role of MTDH in breast cancer metastasis using preclinical models. MTDH-SND1 protein complexes were found to inhibit antigen presentation in cancer cells. This decrease in antigen presentation allows the breast cancer cells to avoid T-cell-mediated immune detection, which is a critical process necessary for the identification of cancer cells by the immune system. Additionally, the researchers showed that high levels of MTDH led to poor cytotoxic T-cell infiltration and activation, thereby inhibiting the immune-mediated destruction of cancer cells. In animals with metastatic tumors that were treated with C26-A6, significant increases in antigen presentation, as well as T-cell infiltration and activation, were observed. Interestingly, C26-A6 treatment combined with anti-PD-1 (an existing cancer immune checkpoint blockade therapy), resulted in an increased inhibition of tumor growth and metastasis compared to treatment with anti-PD-1 therapy alone. These findings suggest that targeting MTDH may enhance the effectiveness of existing immunotherapies used for treatment of metastatic breast cancer.

The results obtained from Drs. Kang and Xing’s BCRP-funded research support potential for a new class of novel therapeutics to inhibit breast cancer progression and metastasis. Additionally, their findings provide preliminary evidence that targeting MTDH in breast cancer cells with a small molecule, C26-A6, can sensitize tumors to immunotherapies and chemotherapies that are currently employed to treat metastatic disease. Taken together, these critical findings have the potential to lead to improved outcomes for metastatic breast cancer patients.

References:

¹Jin, Xin, and Ping Mu. “Targeting Breast Cancer Metastasis.” Breast cancer: basic and clinical research vol. 9, Suppl 1 23-34. 1 Sep. 2015, doi:10.4137/BCBCR.S25460

²Tokunaga, Eriko et al. “Overexpression of metadherin/MTDH is associated with an aggressive phenotype and a poor prognosis in invasive breast cancer.” Breast cancer (Tokyo, Japan) vol. 21,3 (2014): 341-9. doi:10.1007/s12282-012-0398-2

³Wan, Liling, and Yibin Kang. “Pleiotropic roles of AEG-1/MTDH/LYRIC in breast cancer.” Advances in cancer research vol. 120 (2013): 113-34. doi:10.1016/B978-0-12-401676-7.00004-8

⁴Wan, Liling et al. “MTDH-SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors.” Cancer cell vol. 26,1 (2014): 92-105. doi:10.1016/j.ccr.2014.04.027

Publications:

Shen M, Smith HA, Wei Y, et al. 2022. Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD1 therapy in metastatic breast cancer. Nature Cancer 3(1):60-74. doi.10.1038/s43018-021-00280-y

Shen M, Wei Y, Hahn K, et al. 2022. Small molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis. Nature Cancer 3(1):43-59. doi:10.1038/s43018-021-00279-5

Links:

Public and Technical Abstracts: Functional Mechanism and Targeting of Metadherin in Breast Cancer

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