Nobel Prize goes for autophagy research

Print 07 October 2016
Anette Breindl / bioWorld

"Basically, it's not easy to define what will serve humanity."

So said Yoshinori Ohsumi, honorary professor at the Tokyo Institute of Technology, after winning the 2012 Kyoto Prize in Life Sciences for his research.

The Nobel Assembly followed suit in recognizing the importance of Ohsumi's work, awarding him the 2016 Nobel Prize in Physiology or Medicine to "for his discoveries of mechanisms for autophagy."

Autophagy, or the process of self-eating, is an excellent example of a process whose understanding may end up serving humanity in multiple ways. It is now being recognized as a basic cellular process that plays a role in many different diseases.

But when Ohsumi began his research, nearly 30 years ago, autophagy was more or less a research backwater.

The freshly minted Nobelist said that "When I started my work, probably every year 20 or [fewer] papers appeared on autophagy." But "as research into autophagy has expanded, it has become clear that it is not simply a response to starvation. It also contributes to a range of physiological functions, such as inhibiting cancer cells and aging, eliminating pathogens and cleaning the insides of cells."

As a result, there are now several thousand papers a year published on autophagy, and researchers are trying to target the process in disease states including cancer, infectious diseases and neurodegeneration.

Autophagy is a cellular response that attempts to deal with stress, often induced by starvation. When nutrients are scarce, cells will recycle large cytoplasmic proteins and organelles to survive until the situation improves.

INFECTIOUS DISEASE

The process plays a role in infectious diseases, where either blocking or encouraging it can be useful, depending on the exact situation. Some infectious agents, such as Mycobacterium tuberculosis, block autophagy in macrophages to protect themselves from being digested. This ultimately prevents antigen-presenting cells from having anything to present and allows M. tuberculosis to hide itself from the immune system. (See BioWorld Today, Nov. 29, 2004.)

The malaria parasite, on the other hand, uses autophagy to remodel itself during the transition from liver to blood stage of infection and the malaria hydroxychloroquine blocks autophagy.

Cancer researchers have become interested in blocking autophagy because it is one way in which cancer cells can find material to fuel their growth. Autophagy is one of the processes that are linked to the activity of mTOR, a major sensing complex that directs growth decisions according to nutrient availability. When nutrients are plenty, mTOR will inhibit autophagy. Conversely, when mTOR is inhibited, cells can use autophagy as an alternate path to fuel. (See BioWorld Today, May 3, 2010.)

As a result, hydroxychloroquine is currently enjoying something of a second career in oncology. (SeeBioWorld Today, Feb. 29, 2012.)

Everolimus (RAD001, Novartis AG) and Torisel (temsirolimus, Pfizer Inc.), both mTOR inhibitors, are being tested in separate phase I trials in combination with hydroxychloroquine. Other phase I trials are looking at the effects of adding hydroxychloroquine to HDAC inhibitor Zolinza (vorinostat, Merck and Co. Inc.), proteasome inhibitor Velcade (bortezomib, Takeda Oncology Co.), and radiation. And furthest along is a phase II trial comparing Tarceva (erlotinib, Roche Holding AG) with and without hydroxychloroquine in EGFR-mutated non-small-cell lung cancer.

However, just as either blocking or upping autophagy can be useful in infectious diseases, the role of autophagy in cancer is complex.

While established tumors use autophagy to feed themselves, autophagy appears to be a tumor suppressor mechanism earlier in the game.

In a 2015 review article published in Leukemia, researchers from the University of Pittsburgh Medical Center summarized the situation by saying that "during the early phase of tumor initiation, autophagy appears to be suppressed, allowing the emergence of genomic instability. Later in tumor development, autophagy is more active, leading to enhanced cancer cell survival, as described in this review. Therefore, efforts to inhibit autophagy are particularly warranted in established tumors."

NEURODEGENERATION

While autophagy inhibitors are being tested in cancer, at least one cancer drug – Tasigna (nilotinib, Novartis AG) increases autophagy. Tasigna also crosses the blood-brain barrier, and so it is being tested in neurodegeneration, where increasing autophagy may be a promising strategy.

Many neurodegenerative diseases result from the accumulation of misfolded proteins, such as amyloid plaques in Alzheimer's disease, alpha-synuclein clumps in Parkinson's, and misfolded prion proteins. Rare diseases, such as lysosomal storage disorders, also result in part from mutations that lead to the production of proteins that first misfold, and then aggregate. (See BioWorld Today, Sept. 22, 2016.)

One of the problems with such aggregations is that they become too big to enter the cellular trash disposal system that would normally break them down, the ubiquitin-proteasome system. They can still, however, be dealt with via autophagy, which is specialized on larger molecules.

A phase I trial by researchers from Georgetown University showed that in a phase I trial, treatment with Tasigna "increased brain dopamine and reduced toxic proteins linked to disease progression in patients with Parkinson's disease or dementia with Lewy bodies," according to a statement by the university's press office.

The trial also made enough of a splash that the National Parkinson's Foundation weighed in, releasing a statement that Tasigna "had positive results that certainly warrant the continuation to a phase II trial, however it is too early for patients to seek treatment outside the setting of a clinical trial." A phase II trial is being planned currently in the planning stages.

There is preclinical evidence, in neuronal cultures and mouse model, for a number of drugs as autophagy boosters that could be useful for treating both age-related neurodegenerative disorders and those that are due to inborn errors of metabolism. Those drugs include antihypertensive drug Covera-HS (verapamil), Catapres (clonidine), which is both an antihypertensive and a sedative, and multiple others.

It is worth noting, though, that boosting autophagy is unlikely to be a slam-dunk. A 2016 review in the journalBrain included Dimebon (latrepirdine, Medivation Inc.), in a table of "modulators of autophagy in neuronal disease models."

To date, though, that preclinical promise has not shown up in clinical trials. Dimebon's development was discontinued in 2012 after the drug had failed to meet its endpoints in three separate trials for Alzheimer's and Huntington's disease. (See BioWorld Today, April 11, 2011 and Jan. 18, 2012.)

Like many discoveries with truly broad implications, Ohsumi's research into autophagy was driven primarily by intellectual curiosity – hence his warning that it is not easy to know in advance which research will be useful.

In his 2012 interview after winning the Kyoto Prize, Ohsumi said that despite the current drive towards research that is explicitly translational, "you can answer the most basic and important questions about the nature of life through yeasts. My research was able to explain autophagy precisely because I was working on yeasts and could observe them under an electron microscope."

Source

Return