DeBriefing Class and Assignment#4, Cancer2019, 20190228
SubjectLine: Publishing an example of one of my ‘Debriefing of Class’ to DocumentaMoses.org, New Assignment#4, Cancer2019.
Shortened URL: http://bit.ly/Cancer2019_4, I (K Moses) updated this page by revisiting key links and checking on the latest postings, 201905251100.
Note. There is a new link shortening service on the market, Rebrandly, Assignment#4 is findable with the address, http://read.inquiryinquiry.org/Assignment-4 … this is a good service. Rebrandly allows account holders to use their own base domain, here I am using the hosting address for our course, inquiryinquiry.org.
At the End of our meeting I tried to frame an Assignment (#4) for you based on the following:
- (For those who want to immediately get to it, find this on this page: I proposed an Assignment for you with mutp53 and/or wtp53 as the target(s) for a therapy regime, designed by you,)
- Currently the FDA has a beautiful page on FDA approvals in Cancer treatment, www.cancer.gov/news-events/cancer-currents-blog/fda-approvals. National Cancer Institute, Accessed the 25 May. 2019, 20190525. The number of approved uses for ImmunoTherapies is increasing: "T-DM1 Approval Expanded for HER2-Positive Breast Cancer." National Cancer Institute, 25 May. 2019, www.cancer.gov/news-events/cancer-currents-blog/2019/kadcyla-fda-breast-her2-adjuvant.
- See a little bit of history, "FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome | FDA." U.S. Food and Drug Administration, 7 Sept. 2017, www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome.
- Quote From Article: ‘
- ‘Tisagenlecleucel is the first chimeric antigen receptor (CAR) T-cell immunotherapy approved by the FDA.’
- Screenshot of the above quote, https://www.evernote.com/l/AAdI7Hn2hMJB4rEF_iYQ8CYiwtls721gr_k,
I am looking for the appearance of approved therapies directed at mutp53, I am still searching but at this point, no hits I like, look like they clearly work, none, … And I can be wrong, (20190511, Dear Class please do the same, I tried this, Google: FDA AND approved AND "mutp53")
- mutp53 has been frequently proposed as a target for a therapy regime, (For a Review see Yue et al, 2017 … Currently being presented by me, I am using this 2017 paper because I feel it frames a design sensibility very well),
- Citation: Yue et al ‘Mutant P53 in Cancer: Accumulation, Gain-of-Function, and Therapy,’ 2017. https://www.sciencedirect.com/science/article/pii/S0022283617301638?via%3Dihub. I added this reference to our Class Google Folder and here is a direct Google LINK, Yue_etal_2017_mutant_p53_in_cancer.pdf,
- Dear Class in terms of designing you may be interested in this approach, Kumar, R., et al. "Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers." Nat. Commun., vol. 9, no. 1, 26 Sept. 2018, p. 3931, doi:10.1038/s41467-018-05805-1. See, https://www.nature.com/articles/s41467-018-05805-1 (Open Access)
- And reported here, Staff, Science X. "Tapeworm drug targets common vulnerability in tumor cells." Medical Xpress, 18 Mar. 2019, medicalxpress.com/news/2019-03-tapeworm-drug-common-vulnerability-tumor.html.
- We might want to consider that every single one of the 210 new drugs approved by the Food and Drug Administration (FDA) from 2010 to 2016 was developed thanks to NIH’s taxpayer-funded research. See, Cleary et al., ‘Contribution of NIH Funding to New Drug Approvals 2010–2016.’ Proceedings of the National Academy of Sciences 115, no. 10 (6 March 2018): 2329–34. https://doi.org/10.1073/pnas.1715368115, And, https://www.pnas.org/content/115/10/2329
The Assignment: I proposed an Assignment for you with mutp53 and/or wtp53 as the target(s) for a therapy regime, designed by you,
I proposed reference to Figure 3. in Yue et al, 2017, p. 1600, See here, https://www.evernote.com/l/AAcvEJ1RI1JIHLlUzKrqKZ_ksS2TARd8YMU and this text at p. 1601,
"Therapeutic Strategies to Target Mutant p53: Given that mutp53 proteins often accumulate to high levels and exert GOF to promote malignant progression in human cancer, targeting mutp53 has become an attractive therapeutic strategy for cancer containing mutp53 [11,22,23,113]. The main strategies to target mutp53 are restor* ing the wild-type p53 activity and depleting mutp53 protein in cancer (Fig. 3)."
Fig. 3 puts forth a sort of thinking framework: Restore* wtp53, Deplete mutp53 … See, https://www.evernote.com/l/AAcvEJ1RI1JIHLlUzKrqKZ_ksS2TARd8YMU.
- That word "Restore" is an interesting choice consider mutp53 proteins can form a tetramer with wild-type p53, which can block** the function of the remaining wild-type p53 in Tumour Suppression, so "Restore" is a good choice of flexible meaning.
- ** We should check on the status of this blocking activity in the published literature, the most recent citation to this activity is M. Oren, V. Rotter, Mutant p53 gain-of-function in cancer, Cold Spring Harb. Prospect. Biol. 2 (2010) a001107. … which is worryingly old for my (KM) understanding of how vibrant the field is, I will check again,
You can, of course, choose to think outside of this particular box; the Assignment (#4) is for you to propose, design a therapeutic strategy using any source information you wish or anything off the top of your head that uses, "[a]round 50 percent of human cancers harbor p53 mutations [References: 11–14]," See Yue et al., p. 1596. I want you to focus on mutp53 and of course you can discuss this with me, us,
- If you want to see design in action check out, ‘PEPTIDES CAPABLE OF REACTIVATING p53 MUTANTS,’ U.S. Patent Application No. 15/796811 (Filed: 29 October 2017), Publication No. 20180057533 (2019-05-08, the Application status is Pending), https://patents.google.com/patent/US20180057533A1/en, Applicants: Moshe Oren et al.
This assignment is NOT due the 5th of March, we talk about it again on the 5th with a Due Date proposed shortly thereafter, … And sure you can collaborate on this, … Submission via Email, Responses in the Body Text please, SubjectLine: Cancer2019, mutp53_Therapies,
Proposed Due Date: please submit your best work, the deadline is flexible, … before our last class, you should give this plenty of your creativity,
In our meeting, I directed you to check out the TP53 website at http://p53.free/.fr … "after 20 years of existence with more than 4 million pages visited," this site has been updated to http://p53.fr/.
Thanks for coming to our meetings,
Best to you,
p.s. The current version of the Adaptable Rubric is here, we can manipulate this together: http://bit.ly/Adabptable_Rubric,