Montag, 14. Dezember 2015

Optimizing resource use - Chronic toxicity and preclinical studies

This post is related to the idea of "Optimizing resource use by outsourcing of lifespan research" to pet owners and zoos.

What should we study? We're clueless!
We don't understand aging very well. That's the reason why we need to perform both naive screens with novel chemical matter (more on that below) as well as large, high-throughput screens with drugs that target plausible pathways. But what are the plausible pathways if we are clueless?

Well, it's not quite as bad as you may think, since we do have some basic paradigms in aging research. Bluntly put, there's for instance "anti-growth" as well as "mimic CR/dwarfism" (= which usually amounts to an "anti-growth" paradigm). The idea that diminished signalling through a multitude of growth pathways extends longevity has been shown to be true in scores of studies (just recently, ref. 1, 2).

Preclinical studies: how about worms and flies?
Preclinical safety studies presently include cell culture work in human cells as well as rodent models (usually rat) and non-rodent models. The latter often includes dogs and primates (5). From a basic science perspective, we should consider mandating chronic "safety" testing in invertebrates. This would be very useful to biogerontologists, as we can expect to find a reasonable number of life extending drugs by pure chance. On the other hand, it is not clear if such "safety" testing has any meaning for human toxicity. An alternative would be to compel companies to give out the drugs (in a blinded fashion to prevent IP problems) and for the government to perform lifespan testing. This method would work particularly well to test the already available drug libraries. (As of today no free market based incentive exists to develop anti-aging therapies. We won't consider the details here.)

Indeed thousands of failed drug candidates must exist and represent a large untapped source for biogerontology. Modern cancer drugs are particularly promising since they target various growth-related pathways. In 2015 "According to the Pharmaceutical Research and Manufacturers of America (PhRMA), 771 new drugs and vaccines are in development by US companies" just to treat cancer (6). It is difficult to find high quality lists with advanced drugs, but there's one up to date list for lung cancer (7). These lists may come in handy for "smaller" projects like the NIA's ITP. It might also be helpful to think in terms of drug targets and then prioritize the most plausible targets and drugs (8).


Chronic toxicity studies in rats
On the one hand, there is a call to limit the use of 2 year rat carcinogenity testing for compunds deemed safe  by other methods and only to perform it for questionable drugs (3). The other option is to make the tox testing more useful for biogerontologists -  these ideas are not necessarily mutually exclusive.

Reanalyzing all drug toxicity testing performed in the last 3 decades in rats (n=182 drugs):
We propose from these evaluations that compounds that are negative for genotoxicity [e.g. micronucles or Ames test], negative for hormonal perturbation activity, lacking specified histopathologic risk factors for rat neoplasia in [shorter term, smaller] chronic rat toxicology studies, and negative in an alternative six-month transgenic mouse carcinogenicity study need not require a two-year rat carcinogenicity study in the course of pharmaceutical development.

Whether chronic tox testing is continued or limited, I suggest the following rules**:
A. If there is reason to suspect lifespan extension, a chronic rat or mouse study must always be conducted
B. If a study shows a signal towards lifespan extension, the study must always be extended to allow max LS determination.

For example, curcumin is one of the drugs that came up positive in a chronic rat tox study, which was one of the reasons it was chosen for more stringent lifespan testing (and failed). (4) It would have been much simpler if the tox study could have been extended.


References
**The initial idea originated on the imminst fora. I take no credit,

1. Hofmann, J. W., Zhao, X., De Cecco, M., Peterson, A. L., Pagliaroli, L., Manivannan, J., ... & Sedivy, J. M. (2015). Reduced expression of MYC increases longevity and enhances healthspan. Cell, 160(3), 477-488.
http://tpx.sagepub.com/content/39/4/716.full

2. Hofmann, J. W., Zhao, X., De Cecco, M., Peterson, A. L., Pagliaroli, L., Manivannan, J., ... & Sedivy, J. M. (2015). Reduced expression of MYC increases longevity and enhances healthspan. Cell, 160(3), 477-488.

3.
An Analysis of Pharmaceutical Experience with Decades of Rat Carcinogenicity Testing
Support for a Proposal to Modify Current Regulatory Guidelines
http://tpx.sagepub.com/content/39/4/716.full

Toxicology for the twenty-first century
http://www.animalexperiments.info/resources/Studies/Alternatives/Tox--overall.-Hartung-2009./Toxicity-Hartung-2009-Nature.pdf
Notes on animal welfare: The grand majority of animals are killed for food production then followed by toxicologic testing of (industrial and everyday) chemicals but not biomedical research. Crazy people, choose your fire bombings wisely!

History of Chronic Toxicity and Animal Carcinogenicity Studies for Pharmaceuticals
http://vet.sagepub.com/content/50/2/324.full

4. Strong, R., Miller, R. A., Astle, C. M., Baur, J. A., de Cabo, R., Fernandez, E., ... & Harrison, D. E. (2013). Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 68(1), 6-16.

5. https://www.uab.edu/medicine/adda/images/131205%20Tox%20Animal%20Models.pdf

6. "The 2015 Oncology Drug Pipeline: Innovation Drives the Race to Cure Cancer"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489190/

7. A tabulated summary of targeted and biologic therapies for non-small-cell lung cancer.
Simon GR, Somaiah N.
Clin Lung Cancer. 2014 Jan;15(1):21-51. doi: 10.1016/j.cllc.2013.11.009. Epub 2013 Nov 21.

8. Overington, J. P., Al-Lazikani, B., & Hopkins, A. L. (2006). How many drug targets are there?. Nature reviews Drug discovery, 5(12), 993-996.

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