It has been demonstrated that Notch negatively regulates the development of neuroendocrine tumor and small cell lung cancer since the master transcriptonal factors such as Hes1 and Hey1 inhibit the ASCL1, necessary to induce endocrine tumor markers. That is why I think that small molecule activating Notch signaling pathway is promising for patients with those difficult-to-cure tumors. I would like to have your opinion and have an open discussion.
Notch inhibition is actually being currently tested in the clinic for cancer with gamma secretase inhibitors and antibodies to specific Notch receptors. I have never heard of activating Notch as a way to treat cancer.
Inhibiting Notch might be the logical way to deal with neoplasms. So far I have met with no argument for the opposite - agree with Marcia here. What was your way of reasoning, Go?
Well, it depends on the type of cancer. In most of the cancers such as pancreatic cancer, head and neck cancer and breast cancer, inhibition of notch pathway has been suggested to be effective. On the other hand, valporic acid, a well known drug for epilepsy treatment, is known to increase activation of notch with its anti-tumor effect on carcinoid tumors.
Notch signaling activating mutations are strongly associated with many tumorigenic processes, in particular the hyper-activation of the pathway play an important part in the origin of some leukaemias such as the T-ALL´s. It is also true that hypo-activation of Notch has been observed in some other cancers, like it seems to be the case for neuroendocrine and small cell lung tumors. If you treat a patient with a compound that activates Notch signaling, even if you “cure” the individual (for neuroendocrine or small cell lung cancer), you are facing the risk of developing a number of different oncogenic processes in other organs. So, unless you are able to deliver the drug specifically in the mentioned tumour without affecting other tissues (which I would say is not possible nowadays), I would rather think that is not a good idea to treat patients with molecules that activates this pathway.
Thank you everyone for the kindness to give me great opinions. As most of you, I have once thought that Notch inhibitor is a promising therapeutic target, while constitutive activation of Notch signaling renders tumor cells the proliferation and metastatic potentials. However, after the knowledge of the unexpected function of ASCL1 in neuroendocrine tumors, Notch signal pathway plays a role as the tumor-suppressor depending on the tumor types.
I agree with everyone. I have done extensive experiments on neuroendocrine tumors. We have shown in several publications activation of Notch pathway is beneficial to reduce neuroendocrine tumors. However, as mentioned by others, the idea is still good but controversial. Neuroendocrine tumors behave just opposite of other cancers. Animal experiments (S.C) with Notch activators did reduce tumor growth and no sign of other tumors. However, the duration is very short. Also, I noticed that Notch activators increase Notch pathway mainly in neuroendocrine tumors, however, it did not increase the notch in pancreatic cancer or other known notch expressing cancers. Therefore, I believe that the concept is good but it may take years to be accepted by others.
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