The key to finding new targeted drugs for leiomyosarcoma is to know how LMS cells grow uncontrolled. Not only do certain gene mutations drive the growth, but there are gene mutations that limit the body’s own controls on cell growth. This is the case with a tumor suppressor gene called VIPR2. This gene suppresses tumor growth. When it is damaged, a tumor has a better chance of surviving and thriving.
A 2008 study on uterine leiomyosarcoma (uLMS) sequenced 84 tissue samples from several centers. The authors identified reduced expression of four tumor suppressor genes: TP53, RB1, PTEN and VIPR2. VIPR2 is a negative regulator or smooth muscle proliferation. In the 84 samples, VIPR2 was reduced in 96% of the uLMS samples. In addition, those patients with this reduction of VIPR2 in their samples, fared worst outcomes.
More recently, a study published in October of 2017, Integrated genome analysis of uLMS to identify novel driver genes and targetable pathways, also looked at uLMS samples and found that the most frequently affected gene in their uLMS samples was VIPR2 (96%). VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased uLMS cell proliferation. The authors concluded, “These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS.
The 2008 study authors proposed that the drug called Imipramine, could help by upregulating this tumor suppressor gene identified in uLMS. Imipramine (brand name Tofranil) is an antidepressant approved by the FDA. Not only does it help with depression and anxiety, it upregulates VIPR2 expression.
Is Imipramine our next targeted drug for uLMS? This drug has been on the market since the late 1950’s. Any doctor can prescribe this drug for depression or “off-label” for uLMS. We need some controlled studies to find out if it is an effective treatment for uLMS. I have already been discussing this with our sarcoma researchers, urging them to study VIPR2 and Imipramine. We know research is slow. In the meantime, if you are depressed or anxious, you may want to discuss with your doctors using imipramine. It might turn out to be a great two-fer!
More uLMS information
Involvement of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors in the mechanism of antidepressant action. J Mol Neurosci 2008;36:330–338.
Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways. International Journal of Cancer, October 2017 https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.31129
Wikipedia on Imipramine: https://en.wikipedia.org/wiki/Imipramine
Systemic Treatment of Metastatic/Recurrent Uterine Leiomyosarcoma: A Changing Paradigm: The Oncologist 2018;23:1–13