The "cancer gene" can be turned off
The methadherin gene and its protein (MTDH) play a key role in the life of atypical breast, prostate, lung, liver and colon cancer cells. At the same time, MTDH is not important for healthy tissues, so it can be used as a target for cancer treatment with little or no undesirable side effects.
Yibin Kang, an oncologist from Pinston University, has been studying this little-known but dangerous gene for more than 15 years. In a new study on mice and human tissue samples, he reported on an experimental drug aimed at MTDH, which inhibits the growth of cancer with monotherapy, and also significantly increases the effectiveness of chemo and immunotherapy. It is known that cancer metastasis significantly worsens the prognosis of the disease. For example, the five-year survival rate for breast cancer is 99%, and if metastases have appeared – only 29%. Back in 2009, it was shown that MTDH functions at an abnormally high level in breast cancer cells compared to normal cells, and this leads to metastasis and chemoresistance. In 2014, Kahn showed that MTDH is vital for the development and metastasis of cancer. Healthy mice that had MTDH turned off at birth did not differ from the control group, which means that the gene is not required for normal life.
It was soon proven that MTDH is also important for the progression of prostate, lung, liver and colon cancer. It was not possible to disable the MTDH protein directly, but two protrusions were found on its surface, which are embedded in two pockets on the surface of another protein, SND1. MTDH and SND1 are closely related and depend on each other. The researchers hypothesized that if they broke this connection, the effects of MTDH would be neutralized. They found a molecule that can fill one of the two deep pockets on SND1, preventing the proteins from coupling.
If we compare SND1 with the keyhole into which the key is inserted (MTDH), then the new connection is another key that takes up space, leaving MTDH free.
Two mechanisms and no side effects
Kang and his colleagues have shown that MTDH has two main properties: it helps tumors survive under the stress they usually experience as they grow or during chemotherapy treatment, and also drowns out alarm signals emanating from tumor-affected organs. The MTDH-SND1 duo suppresses the signaling pathway that activates the immune system against aggressor cells.
With the help of an experimental drug, the researchers reactivated the alarm system. Subsequently, it makes the tumor much more susceptible to both chemotherapy and immunotherapy.
In normal tissues, healthy cells are usually not stressed and do not send signals that the immune system can recognize as alarming, so MTDH is not necessary for normal tissues, and the new drug is practically non-toxic. In experiments on mice, not a single side effect was noted.
Kahn and his group are working to optimize the compound to achieve a higher affinity and a lower effective dose of the drug.
Articles by M.Shen et al. Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis and M.Shen et al. Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer published in the journal Nature Cancer.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Princeton University: New cancer therapy from Yibin Kang's lab holds potential to switch off major cancer types without side effects.