NOTCH4 inhibitors to combat tamoxifen resistance

Lojo

Possibility of using NOTCH4 protein inhibitors to counter tamoxifen (or other anti-estrogen treatment)
resistance in tumors.

http://www.sciencedaily.com/releases/2015/09/15091...

JohnSmith

I was just about to start this thread and I saw yours, so I'll add to it. This is important because of its connection to Cancer Stem Cells (CSCs). It's also important because so many take Tamoxifen and other anti-estrogens.

Additional Source detail:
http://www.cell.com/cell-reports/pdf/S2211-1247(15)00947-X.pdf
"Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity"

Highlights
- Anti-estrogen therapies selectively enrich for Breast Cancer Stems Cells (BCSCs) and activate Notch signaling
- Notch pathway activation and ALDH1 predict for anti-estrogen treatment failure
- Targeting of Notch4 reduces the population of BCSCs
- Notch inhibitors might prevent relapse or overcome resistance in ER+ tumors. [The good news is that NOTCH inhibitors are already in a variety of clinical trials].

excerpt from article: "Short-term treatment with anti-estrogen drugs decreased tumor growth, but it increased the activity of breast cancer stem cells".

Note: The topic of cancer stem cells (CSCs) is very interesting. Stem cell scientists (like Dr. Max Wicha - great video) have said that measuring drug therapy success by tumor shrinkage may be flawed. The reduction of bulk tumor cells from drug therapy is obviously good, BUT conventional therapies (chemo & rads) are ineffective against the sub-population of cancer stem cells. It essentially might explain recurrence in ALL cancer. This current hypothesis says that cancer evolves, progresses, and metastases from cancer stem cells. So despite the tumor shrinkage, CSCs might be re-fueling the tumor. Again, this is the cancer stem cell theory. It seems plausible and if true, hopefully researchers will confirm asap, so they can re-focus efforts on the proper experiments.

Here's my questions for the UK Researchers:

1. What subtype(s) of breast cancer were used in the research?
2. Menopause status (pre vs. post) seems to be play in ever increasing role on how tumors behave. Is this is the case with BCSCs, and which Menopause cohort was represented in this research?
3. Can the data from the existing Notch inhibitor clinical trials be leveraged to validate these research findings?
If not, when is a clinical trial launching to confirm this research?
4. How much toxicity should be anticipated when combining Tam and Notch inhibitors?
5. Is Notch4 a gene tested for expression? or is it tested for gene mutation? For example, FoundationOne's pan-cancer gene assay, tests for Notch1, Notch2, Notch3, but nothing listed for Notch4.
6. Beyond ER+, did the research parse data among breast cancer subtypes (i.e. Ductal vs. Lobular, etc)? If so, did Notch4 expression occur more in one of the subtypes?
7. Will this research be presented at SABCS in San Antonio this upcoming December?

mike3121

I read this. Interesting and hopeful. My wife has just one more cancer to go, a small kidney cancer tumor. She's had chemo and is taking tamoxifen for her ER+ BC and radiation for her triple negative metaplastic BC in her lymph nodes. I looked up NOTCH4 protein inhibitors on the web. Actually articles about his go back to 2008. I'm sure if this was some that good we'd have had phases trials by now and maybe even a product out.

Lojo

I haven't read this thoroughly, but another (earlier) look at the NOTCH pathway in BC

http://www.nature.com/oncsis/journal/v2/n8/full/on...

Lojo

And one more - 2007 article on gamma secretase inhibitors (GSI) and notch signaling http://cancerres.aacrjournals.org/content/67/5/187...

JohnSmith

BCO added this news to their thread "Breaking Research News from Breastcancer.org"

"Study Offers New Reason Why Some Cancers Resistant to Hormonal Therapy"
A very early study suggests that silencing the NOTCH4 pathway in a breast cancer can make the cancer respond to hormonal therapy again if it's become resistant.

Excerpt from the news: "NOTCH4 testing isn't widely available yet. Still, if you've been diagnosed with hormone-receptor-positive breast cancer that has stopped responding to hormonal therapy, you may want to ask your doctor about this study. There may be a clinical trial studying hormonal therapy resistance that might be a good fit for you and your unique situation"