In Search of the Ultimate Cause of Cancer Death and Survival

Here’s some interesting science to follow and think about in the context of mCRPC treatment. – how cancer and cancer treatment will influence and even accelerate aging – and what we can do about it.

My institution, the University of Minnesota, recently launched a “Medical Discovery Team on the Biology of Aging” a program that brings together clinicians, scientists and policy experts around this theme of aging. Although I am not part of this team, I was able to attend an open seminar that they held recently, and we are planning some collaborations around cancer related issues. What follows are my thoughts on some of the discussions that came out of this very enlightening seminar.

Consider not only cancer but also diabetes, cardiovascular disease, arthritis, and Alzheimer's dementia, the veritable rogue's gallery of conditions that plague the elderly. While we think of them as distinct entities, they all share a common underlying process – cellular aging. The treatments we use to treat cancer can accelerate this process so those of use radiation, chemo or hormonal therapy to treat prostate cancer are well served to be thinking about it.

But how does cellular aging start?

There are four fundamental mechanisms leading to biological aging, as described by Jim Kirkland of the Mayo Clinic:
  1. Inflammation
  2. Cellular Senescence
  3. Macromolecular dysfunction ( e.g. changes in DNA, Telomeres etc)
  4. Stem Cell and Progenitor Dysfunction
These processes interact. One process ( like inflammation) can initiate one of the others, like cell senescence, and vice versa. Let’s focus on cellular senescence, as it is where much of the science is leading us at present.

Senescent cells are like zombies. They don’t die, but they spread death. They are a damaged cell or group of cells within a tissue that has initiated a cascade of events that affect the underlying tissue, whether it be a joint, a muscle, the heart or the brain.  Even though they may be a minority of cells within a tissue compartment, they secrete a variety of factors that result in further tissue destruction and cell death.  To use another autumnal simile – they are like the rotten apples that spoil the bushel.  Kirkland and his team have shown this experimentally by injecting senescent cells into mice bone or joints and observing that this “infects” nearby healthy cells and those cells will age in an accelerated

What does this have to do with prostate cancer? A lot, in fact.

One of the great joys of taking care of patients with prostate cancer is that many patients survive a long time on treatment, and we now have several treatments that are useful. But consider hormonal therapy by itself, and picture a patient before any treatment and after, let’s say, 6 years of ADT. We now know that about this time is when we will see things like osteoporosis, fat accumulation and muscle loss, not to mention the looming possibility that the patient may be experiencing an accelerated cognitive decline from the ADT.

These may all be the effects of the process of cellular senescence that is induced by the treatments.

As a Philosophy student, we learned about the two different types of causation – proximate cause and ultimate cause. While a process may have a proximal cause that started it all, in many situations, there is an ultimate cause that precedes it. A classic example is the assassination of Archduke Franz Ferdinand in Sarajevo in 1914. This killing was the proximate cause of WWI, but, as any history student knows, the ultimate cause of WWI was the entangling alliances that formed as a result of prior wars, European Aristocracy, and trade agreements, turning the European continent of a century ago into a powderkeg that the assassination ignited.

So, while the loss of healthy cellular and calcified bone is the proximate cause of osteoporosis, what is the ultimate cause of bone loss? It is likely that cellular senescence is that ultimate cause.

A number of processes can initiate a cell to be senescent and in our world of prostate cancer

Consider first the treatments that we give to our patients. Radiation, hormonal therapy, chemotherapy etc. All of these treatments attack cancer via biological insult but they also exert a biological insult on the normal cells. When we treat patients we cause some cells to become senescent cells. 

These cells then go on to secrete factors like chemokines, cytokines, growth factor and matrix remodelers that accelerate the aging and weakness of normal tissues- thus affecting the patient

The upside here is that aging researchers are focusing on these cellular rotten apples to be targeted for both prevention and intervention of these ills. The hypothesis is that impeding one of these mechanisms will have collateral benefits on the other -for example reducing inflammation will reduce cellular senescence.

How can we incorporate this into our cancer research?

  1. Develop biomarkers for cellular senescence and incorporate them into our studies. What if a certain therapy has marginal antitumor effects but accelerates senescence? This might account for a lack of survival benefit in some studies. We should know that. There is some preliminary work being done on this biomarker development.
  1. Establish and validate the relationship, if it exists, between the objective cellular and biochemical findings of cellular senescence and patient-reported outcomes. (e.g. start by hypothesizing that this relationship exists). Do patients who are on therapies that accelerate senescence feel or function less well than those on other approaches? Are there genetic factors that predispose one group of patients to accelerated cellular senescence while sparing others? This may not be that challenging to figure out.
  1. Rigorously and prospectively test “low lying fruit” approaches that may reduce cellular senescence without negatively affecting disease control. One of the leading candidates is physical exercise. This is already being studied in mCRPC where the epidemiologic data suggests that patients with prostate cancer who exercise live longer and are less likely to die of prostate cancer than those who do not.
  1. Consider testing pharmacologic approaches that may be useful in the situation where lifestyle approaches may fall short. A new class of drugs that target and kill senescent cells, called senolytic therapies, is emerging. Interestingly, these drugs are familiar to those of us in oncology. In a recent publication in Nature Medicine it was demonstrated, in mice, that the administration of oral dasatinib ( a drug used in chronic myelogenous leukemia)  plus quercetin ( a plant-derived flavonoid), reduced the burden of senescent cells in adipose tissue ( where senescent cells had been implanted) and improved the survival of the mice.
Human testing is a long way away as continued mechanistic and dose-related work needs to be done, but at least we are beginning to see what the targets are and how we might be able to hit them. Watch this space.

  1. Let us not forget that cancer cells themselves may be the biggest cause of senescence! If we can focus on that we can evaluate the balance between how cancer causes senescence as well as cancer therapies. If we can reduce the ability of cancer cells to create senescent cells, would that be enough to reduce or delay death from cancer itself?
Reference: Xu et al. Nature Medicine volume 24, pages1246–1256 (2018)

Written by: Charles J. Ryan, MD