Preventing Cancer Metastatis

Cancer biologist Yibin Kang has disabled a key cancer gene MTDH in mice and in human tissue. A human treatment will be ready for human trials in a few years.

This could be the key to preventing or stopping cancer metastasis which is the primary cause of death due to cancer.

99% of breast cancer patients survive five years after diagnosis, only 29% do if the cancer has metastasized, according to current numbers from the National Cancer Institute.

Nature Cancer – Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis

Nature Cancer – Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer

Two mechanisms, no side effects
Kang and his colleagues have shown that MTDH has two primary mechanisms: it helps tumors survive stresses they commonly experience as they grow or under the treatment of chemotherapy, plus it muzzles the alarm cry coming from organs invaded by tumors.

Our immune system is designed for defense, not offense: If it doesn’t know a cell is an invader or is under attack, it can’t send help. The MTDH-SND1 duo suppresses the pathway that presents cancer cells’ danger signal to the immune surveillance system.

“Now, with this drug, we reactivate the alarm system,” Kang said. Subsequently, the drug makes tumors much more susceptible to both chemotherapy and immunotherapies. “In normal tissues, healthy cells are usually not under stress or presenting signals that can be recognized as foreign by the immune system, so this is why MTDH is not essential for normal tissues. In essence, MTDH is a quintessential ‘cancer fitness gene’ that is uniquely required by malignant cells to survive and thrive.”

He continued: “Internally, the tumor cell needs MTDH to survive, and externally, it needs it to hide from the immune system. So you have one drug that disables these two important mechanisms — survival and escape — of the cancer cell. And the most important thing is, the drug has very little toxicity. When we tested it in mice, there were no side effects at all. That’s the best of all worlds: two mechanisms attacking a tumor, very few side effects on normal tissues, and best of all, this is not for one specific kind of cancer, but for all major kinds of cancers.”

Abstract – Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis
Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein–protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH–SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

Abstract – Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH–SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH–SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH–SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.

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