RE:RE:RE:RE:RE:New article published Cash always wins, I fully agree if the drug shows efficacy in bigger groups of patients that should be their target. I speculated while ago also what if what if the ratio of conjugation to the receptor is high enough so they can target lower stages of cancer with less expression of sortilin. That would be even a bigger trade off as not only the market gets bigger but also patients stay on the drug longer due to longer life expectancy.
qwerty22 wrote: "I still belive that the key to great efficacy results will be selection of patients with cancers overexpressing sortilin"
Sure. And the key to higher sales is the largest possible target population. It's a trade-off where I believe you aim for the largest population that gives an acceptable ('approveable') response. Cash wins! So if efficacy looks weak they might be forced to target the drug to a sub-population of strong Sortilin expressors. But if it's good then target the largest population. To work out which it will be you first have to explore the whole population.
Padcev is a useful example, it got approved without reference to it's target molecule and only now is research looking at the impact of the level of their target on efficacy. That's because their efficacy numbers in the whole population are acceptable.
jfm1330 wrote: The link between sortilin and the metastatic potential was known in breast cancer. In this article that I had already given the reference of, when I looked into Sortina's approach, they made experiments on a specific type of TNBC, a subtype called ER-alpha-positive brest cancer. I still belive that the key to great efficacy results will be selection of patients with cancers overexpressing sortilin. I understand the FDA asked then in the phase Ia to not screen for it, to show that sortilin overexpression is needed for efficacy, but in the end, this plaform will need a convenient tool to quickly assess sortilin expression.
https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-018-1060-5
Interestingly, sortilin has been associated with metastatic potential in breast cancer [17] and is highly expressed in breast cancer cell lines compared to non-tumorigenic breast epithelial cells [17].
Results
In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ERα-negative breast cancer as well as in ERα-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin.
Wino115 wrote: Would like to read this too. I think they did show us the photos of the metastasizes on lung samples which backed up their statement (the pre and post administration on Th1902). But you're right, they never specifically identified lymph node metastices for mTNBC. From what I gather, that is the most prevalent location. Would be interesting to know if somethings happening in the lymph nodes that ramps up even more SORT1 in the tumor environments. If someone gets the paper, post it or the link. You could use the old THTXProxy email address too.
qwerty22 wrote:
Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases.
Sounds like that would be some completely new data we havent seen or heard about before. I can't find the full paper though.