Hi, i received today the immunohistochemical report from my son's biopsy. He has brain ATRT cancer. It shows very interesting expressions in the tumor cells. I need your opinion about which repurposed drugs will you use to attacjk these vulnerabilties:
B7H3: Positive in more than 90% of tumour cells.
-pS6: Positive in more than 80% of tumor cells
-Bcl2: Positive of del 20% of tumor cells
-pERK: Positive in 60% of tumor cells
-PD-L1: Negative
- SPARC: Positive in more than 90% of tumor cells
-PARP: Positive in more 90% of tumor cells
-CDK4: Heterogeneus positivity, 40-70% of tumor cells
-EGFR: Negative
I don't know if some of you have used this kind of findings to determine your protocols.
I am not familiar with pERK, PARP or pS6 and its possible inhibitors
For example, pS6 seems to be activated which may be a correlate for a high activity of the mTOR pathway (which may be inhibited by mTOR inhibitors in several tumor entities). What Mtor do you think it can work well)
pERK is also activated which may hint to a high activity of the MAP kinase pathway (which may be inhibited by MAPK inhibitors). Which ones do you know?
CDK4 is a cell cycle checkpoint protein which seems to me moderately activated (may be inhibited by CDK inhibitors in several tumor entities; which ones do you know?
Thanks
I am very sorry to hear of your son's health difficulties. Here are some ideas:
Niacin
Researchers study Vitamin B3 as potential treatment for deadly brain tumour
https://cumming.ucalgary.ca/news/researchers-study-vitamin-b3-potential-treatment-deadly-brain-tumour
Niacin supplementation restores the number of Treg cells
https://www.sciencedirect.com/science/article/pii/S1074761313005645
Honokiol/Magnolol combination
In a xenograft mouse model, the Hono-Mag combination proved superior to standard Glioblastoma
treatment with Temozolomide. Glioblastoma is a fast-growing malignant brain tumor.
https://synergiesforcancertreatments.blogspot.com/p/honokiol.html
Sodium Phenylbutyrate
Could be useful as an HDAC inhibitor or Glutamine depletion
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474985/
This might include useful information on the different epigenetic subgroups:
https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(16)30035-6
Liquid aspirin
https://www.scientistlive.com/content/breakthrough-brain-tumour-research
Professor Geoff Pilkington
https://www.port.ac.uk/about-us/structure-and-governance/our-people/our-staff/geoff-pilkington
List of CDK inhibitors
https://www.researchgate.net/figure/List-of-CDK-inhibitors_tbl1_267393952
I'm including @daniel to notify him of your post
This might include useful information on the different epigenetic subgroups:
https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(16)30035-6
I am reading the above paper and this already stands out for one of the 3 subgroups they have identified.
MITF inhibition could be used as a therapeutic principle to target ATRT-TYR tumors.
In this paper ( https://www.sciencedirect.com/science/article/pii/S0022202X15371141) about Melanoma the researchers say
"The only pharmacological approach that suppresses MITF is the use of HDACi, which
shows anti-melanoma efficacy both in vitro and in xenograft models (Yokoyama et al., 2008).
Two histone deacetylase inhibitors, LBH589 (panobinostat) and valproic acid (vorinostat),
are currently evaluated in clinical trials (ClinicalTrials.gov). Recently, we have shown
that several natural compounds affecting heterogeneous populations of melanoma cells either
increased or reduced the MITF transcript level (Sztiller-Sikorska et al., 2014)."
In my initial response to your post, I mentioned Phenylbutyrate, which is also an HDAC inhibitor (HDACi), as is valproic acid. So that certainly is a valid treatment option IMO, especially considering the very low toxicity of such treatments.
Another interesting bit of information is that "BCL2 promotes angiogenesis through the signal transducer and activator of
transcription 3–mediated (Kaneko et al., 2007) or HIF1-mediated upregulation of vascular endothelial growth factor"
Luteolin could be useful here ( https://pubmed.ncbi.nlm.nih.gov/28264627/).
Fisetin
Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels
"Genes that are highly expressed in almost all ATRTs compared with normal brain included those encoding components of the PRC2 complex such as EZH2, SUZ12, and EED, confirming previous reports that suggest an antagonistic function of the SWI/SNF complex and PRC2 complex members and supporting the need for investigating treatment strategies
that employ PRC2/EZH2 inhibition. Other drug targets overexpressed across ATRT subgroups include AURKA and HDAC1/2.
In addition, VEGFA (upregulated in ATRT-TYR), CDK6 (upregulated in ATRT-SHH), and ERBB2 (upregulated in ATRT-TYR
and ATRT-MYC) represent potential subgroup-specific drug targets (Figure S1E). These results show that ATRTs are biologically heterogeneous despite sharing a loss of SMARCB1 function as the common tumorigenic event."
https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(16)30035-6
"Genes that are highly expressed in almost all ATRTs compared with normal brain included those encoding components of the PRC2 complex such as EZH2, SUZ12, and EED, confirming previous reports that suggest an antagonistic function of the SWI/SNF complex and PRC2 complex members and supporting the need for investigating treatment strategies
that employ PRC2/EZH2 inhibition. Other drug targets overexpressed across ATRT subgroups include AURKA and HDAC1/2.
In addition, VEGFA (upregulated in ATRT-TYR), CDK6 (upregulated in ATRT-SHH), and ERBB2 (upregulated in ATRT-TYR
and ATRT-MYC) represent potential subgroup-specific drug targets (Figure S1E). These results show that ATRTs are biologically heterogeneous despite sharing a loss of SMARCB1 function as the common tumorigenic event."https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(16)30035-6
Hence the use of an autophagy inhibitor looks like a good option. Chloroquine could be used and has proven to extend life in glioblastoma patients. "Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Median survival after surgery was 24 months for chloroquine-treated patients and 11 months for controls." https://www.ncbi.nlm.nih.gov/pubmed/16520474
Summary of the above and some additions.
Honokiol/Magnolol combination Ref
Sodium Phenylbutyrate HDAC inhibitor
Valproic acid HDAC inhibitor
Butyrate (sodium butyrate or tributyrin supplementation, the granules are easy to take for a small child) HDAC inhibitor
Aspirin/Liquid aspirin Ref
Luteolin BCL-2 inhibition Ref
Fisetin decreasing Mitf + BCL-2 inhibition Ref
Chloroquine autophagy inhibitor ref ref
Niacin Ref
Baicalein and Artemisinin as anti-angiogenic could be useful.
Ellagic acid & Quercetin CDK6 inhibitors Ref Ref
Hope this helps, and best of luck.
Hi JOhan, thanks for the fast reply.
Do you have experience with ATRT?
I have used Chloroquine and phenylButyrate and a few others ...
Yes, the cell magazine article was the first review of genomics for ATRT although then it is not used in the clinics for different treatments when the kids have the different subtypes.
I don't know which tumour subtype my son is now, it was not specify it in the study
Given that SPARC and PARP, PS6 and CKD4 are the most altered, i will add inhibitores in those lines. Which in resumen you think could be the best inhibiores in those 4 categories?
Drugs & Therapeutics for Atypical Teratoid Rhabdoid Tumor (ATRT)
https://malacards.org/card/atypical_teratoid_rhabdoid_tumor#therapeutics
Ivermectin results in decreased expression of B7H3 (CD276).
https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=1604282#geneChemicalInteractionAnnotations
Resveratrol results in decreased activity of PS6 (RPS6).
Ivermectin results in decreased expression of PS6 (RPS6).
https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=735279 #geneChemicalInteractionAnnotations
Sodium selenite results in decreased expression of PERK (EIF2AK3).
Acetylcysteine (NAC) results in decreased expression of PERK (EIF2AK3).
4-phenylbutyric acid (Sodium phenylbutyrate) results in decreased expression of PERK (EIF2AK3).
https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=1354090 #geneChemicalInteractionAnnotations
Resveratrol results in decreased expression of SPARC (Osteonectin).
Losartan results in decreased expression of SPARC (Osteonectin).
L-Ascorbic acid 2-phosphate results in decreased expression of SPARC (Osteonectin).
https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=731035 #geneChemicalInteractionAnnotations
Sodium selenite results in decreased activity of PARP1.
Fisetin results in decreased activity of PARP1.
Myricetin results in decreased activity of PARP1.
Niacinamide results in decreased activity of PARP1.
Quercetin results in decreased activity of PARP1.
Resveratrol results in decreased expression of PARP1.
Ivermectin results in decreased expression of PARP1.
https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=1345118#geneChemicalInteractionAnnotations
Simvastatin results in decreased activity of CDK4.
Genistein results in decreased activity of CDK4.
Epigallocatechin gallate (EGCG) results in decreased expression of CDK4.
Berberine results in decreased expression of CDK4.
Aspirin results in decreased expression of CDK4.
Celecoxib results in decreased expression of CDK4.
Butyric Acid results in decreased expression of CDK4.
Vitamin K2 and K3 results in decreased expression of CDK4.
Niclosamide results in decreased expression of CDK4.
Lycopene results in decreased expression of CDK4.
Hesperetin results in decreased expression of CDK4.
Gingerol results in decreased expression of CDK4.
Gamma-tocopherol results in decreased expression of and results in decreased activity of CDK4.
https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=732061 #geneChemicalInteractionAnnotations
Hi JOhan, thanks for the fast reply.
Do you have experience with ATRT?
I have used Chloroquine and phenylButyrate and a few others ...
Yes, the cell magazine article was the first review of genomics for ATRT although then it is not used in the clinics for different treatments when the kids have the different subtypes.I don't know which tumour subtype my son is now, it was not specify it in the study
Given that SPARC and PARP, PS6 and CKD4 are the most altered, i will add inhibitores in those lines. Which in resumen you think could be the best inhibiores in those 4 categories?
No, I don't @oscarmon. My father in law had a recurring glioblastoma, a very aggressive brain cancer, 20 years ago and ever since I've been interested in ways how to improve what medicine has to offer. Because clearly there are ways. I've written on his recovery here:
https://synergiesforcancertreatments.blogspot.com/p/17-year-glioblastoma-survivor.html
If anything I would focus on synergies and combinations.
Given that SPARC and PARP, PS6 and CKD4 are the most altered, i will add inhibitores in those lines. Which in resumen you think could be the best inhibiores in those 4 categories?
Have you seen the list of inhibitors that @aliml2 compiled? I noticed quite a few of the substances I mentioned above appear in this comprehensive list of inhibitors that could be useful based on the results of the genetic profiling of your son's tumor. For example Fisetin for decreasing Mitf + BCL-2 inhibition, for PARP inhibition. Butyric Acid for CKD4 inhibition etc. So there are overlapping mechanisms that could be beneficial.
