Wino115 wrote: Very interesting find - thanks for sharing. There's a lot of pertinent info. We've been discussing this aspect and they reiterate what we had already understood to be the case on normal vs. cancer cells.
"Previously, it has been reported that only 10% of total sortilin could translocate to the surface of normal cells while 90% remained in cytoplasmic organelles such as trans-Golgi-network and vesicles (
33,
34).
Such significant variation in cell surface expression of sortilin between normal and cancer cells makes sortilin an ideal target for cancer diagnosis and therapy. Significant expression of VEGF has been reported to be associated with low-grade bladder carcinoma (
9), which would be a good candidate to be used along with sortilin as a prognostic and therapeutic marker. So, concurrent use of anti-sortilin and anti-VEGF anti-bodies for targeted immunotherapy of bladder carcin-oma is suggested.
The overexpression of sortilin and its clinicopathological role in cancer has been reported in different types of human solid cancers, including breast (18, 35, 36), neuroendocrine (20), ovarian (25, 37), colorectal (38), and hematological malignancies such as chronic lymphocytic leukemia (CLL) (39) during the last decades." They go on to discuss the many ways sortilin, cancer and cell death are linked, but possibly in very unique ways for each type of cancer. It makes the field both exciting, and one where you get the sense there may not just be one answer around dosage, frequency, type of chemo, etc... Over time, in various Phase 2 and 3 studies, one would probably test out a number of different possibilities more customized to each type versus the 1b basket where they're just trying to see efficacy early on without further customization around treatment. They state:
"
The mechanisms by which sortilin facilitates oncogenesis and cancer progression are completely different in various cancer cells. For instance, the function of sortilin in transport of neurotensin as a peptide that induces tumor growth and proliferation has been well documented in pancreas, colon and prostate cancers (
43,
44). A similar study showed that the internali-zation of neurotensin by sortilin induced migration of human microglial cells through the stimulation of both MAP and Pi3-kinase-dependent pathways (
45). Other studies demonstrated that cooperation between sortilin and TrkA facilitates the invasion of breast carcinoma by activating Akt and Src molecules via binding with the cancer-accessory factor of proNGF."
They mention the relationship around cancer stem cells as another positive element and conclude by stating exactly what THTX are doing!
"
Altogether, it seems that sortilin is playing a mediator role in different cancer progression pathways. In case of overexpression of tumor markers such as sortilin with low expression in normal cells, a conjugation of antibody with chemical drugs (antibody-drug conju-gates, ADC) in the format of either mono- or multi-targeting is proposed." I suppose one thing we can conclude is that according to numerous primary research investigators, the sortilin cancer axis is highly fertile ground for experimenting and trying to elucidate the function, possibilities, and challenges. You do begin to understand that THTX is very much at the forefront of taking that lab idea into the real world. Exciting times ahead!