Crowdfunding Progress Towards a Universal Therapy for All Cancers: an Interview with SENS Research Foundation Scientist Haroldo Silva

As you might have noticed, the SENS Research Foundation is presently asking for your support in a crowdfunding campaign that aims to close in on a universal therapy capable of effectively treating all types of cancer, one based on blocking telomere lengthening. As is often the case, the SENS network is here using philanthropic donations to pick up necessary work that hasn't been taken on by the rest of the community, so as to unblock progress. The scientist who will lead the work is Haroldo Silva; he has been focused on this particular branch of cancer research for some years now, and below you'll find a short interview that covers some of his thoughts on the field and on this effort in particular.

I should emphasize that this SENS initiative is an important component in efforts to completely change the way in which the research community approaches the treatment of cancer. The cancer research community suffers from a high level strategy problem: the majority of treatments are only applicable to a small number of cancer types, out of the hundreds of known types, and the majority of new technology platforms under development will be just as expensive to adapt to a different type of cancer as to build in the first place. A much more efficient approach is needed, as there are only so many researchers and only so much funding in the world. As Silva describes below, blocking telomere lengthening is the most efficient of possible better approaches: all cancers must lengthen their telomeres in order to grow, and abuse a small number of target mechanisms in order to do so. These mechanisms, telomerase and alternative lengthening of telomeres (ALT), are very fundamental to cellu lar biochemistry. If they are turned off, it is expected that there is no way for a cancer to evolve around that dead end.

A cure for all forms of cancer is important today, but will become much more important in the future. Cancer stems from mutational damage to cells, and I believe that repair of random nuclear DNA damage scattered across all of our cells is going to be one of the more challenging operations to carry out on human biochemistry. So far no-one has come up with a methodology that is more plausible than the types of advanced nanorobotics requiring a mature molecular manufacturing industry: atomic-scale machinery to visit every cell, analyze, and repair DNA. All sorts of quite effective rejuvenation therapies are going to emerge long before it is possible to fix that problem: some are being worked on by startup companies even now. Thus the future of health in our lifetimes will involve partially rejuvenated people living actively for decades longer than they would otherwise have done, bearing a high load of mutational damage, and with much more active stem cell populations. This is a recipe for a lot of cancer, so the research community had better come up with something better than the present approach - and it is very much in our interest to aid the most promising efforts. To the extent that the SENS Research Foundation and allied researchers are supported in building ways to safely block telomere extension in cancerous cells, we can look forward to truly universal therapies that can be applied to all cancers.

You've been working with the SENS Research Foundation for a while now. How did you get involved in this grand endeavor? What drew you to the fields of aging and cancer?

Early in my college career I became interested in developing technologies that could substantially improve human health and so I majored in Biomedical Engineering with a particular focus on cardiovascular diseases. In graduate school at UC Berkeley, I became more directly involved in aging research by studying the behavior of stem cells from muscle tissue as a convenient model for understanding genetic and age-related diseases. While at Cal, I attended a seminar on campus by Aubrey de Grey on the SENS approach to combating the diseases and disabilities of aging, which drew me to the SENS Research Foundation. Since 2013, I have led the OncoSENS team on our project aimed at treating and preventing cancers that grow by relying specifically on the telomerase-independent Alternative Lengthening of Telomeres (ALT) mechanism. Of course my research endeavor is only one strand of the seven outlined by Aubrey de Grey in Ending Aging, but if we can tackle this major societal burden know n as cancer we can potentially improve the health and life spans of millions of people worldwide.

Controlling cancer and ALT: could you outline your research, and how it fits into the bigger picture? Why is this important?

Cancer is truly a disease of the elderly. Both incidence and death rates grow exponentially with age. And as the population ages globally, according to estimates by the World Health Organization, there will be 21.4 million new cases of cancer worldwide in 2030, which is a whopping 52 percent increase over the 14.1 million cases in 2012. Unfortunately, during the same time span, the number of cancer-related deaths worldwide is expected to increase by 61 percent, from 8.2 million to 13.2 million. Therefore more than 34 million people could be alive and healthy in the year 2030 alone if we succeed in eradicating cancer from our lives!

To accomplish the noble goal mentioned above, our strategy is to attack the single characteristic that virtually all cancer cells have in common: The ability to maintain or elongate telomeres. Every time a cell divides its telomeres, or the DNA sequences at the very ends of each chromosome, get shorter and shorter until the cell is no longer able to replicate. At that stage a cell can either remain dormant or senescent or simply die. Cancer cells on the other hand are able to bypass this natural limitation by replacing telomeric sequences lost with every cell division. There are only two currently known ways for cancer cells to accomplish telomere maintenance. One of these mechanisms relies on expression of an enzyme called telomerase and the other is termed Alternative Lengthening of Telomeres (ALT), which is completely independent from telomerase activity. Our current efforts are focused solely on the ALT pathway.

Our collaborator in Australia, Dr. Jeremy Henson, discovered and published about 7 years ago that ALT cells contain a unique DNA structure that is circular, partially double-stranded and composed of telomeric DNA sequences and he named those structures C-circles. His pioneering work showed that the amount of C-circles in ALT cells correlates directly with the level of ALT activity performed by these cancer cells. However, the method used in the study to detect these C-circles was not amenable to automation and large-scale investigations. Through our collaboration with Dr. Henson, we have developed a high-throughput method to detect C-circles in ALT cancer cells, which enables us to screen thousands of small molecules very quickly and analyze their impact on ALT activity. Once we identify particular drugs in our screens that can inhibit ALT activity, these drugs can potentially be develop further into treatments for ALT cancers.

Given that you have developed a way to speed up all this testing, if you raised the stretch goal of 200,000 in the present fundraiser, what would that really mean for the science?

Raising 200,000 would allow us to test all of the 115,000 drugs in the diversity compound library. This particular drug library was specifically designed to include not only a broad range of chemical structures but also virtually every drug already approved for clinical use worldwide. Using this library will dramatically increase our chances of identifying a potential lead candidate for further testing and validation. Moreover, if one or more lead candidates comes from the pool of drugs already deemed safe and effective for other clinical applications, we can potentially re-purpose these drugs for the treatment of ALT cancers. The advantage here is that such compounds have already been through extensive clinical trials and have a history of use in patients, which significantly lowers the barrier for approval in other disease contexts.

In the short term, this amount of funds would help validate our assay as a bona fide tool for high-throughput screening of ALT-specific phenomena. Our approach could be applied to any other drug library as well as to investigate genes and molecular signaling pathways involved in the regulation of ALT activity. The field of ALT cancer research can definitely benefit from such enabling technologies. In the long term, the massive amount of knowledge as well as tangible strategies capable of tackling the ALT mechanism gained in the context of cancer will inevitably lead to novel therapies that will help millions of patients around the globe. We really mean it when we say we want to "Control ALT, Delete Cancer" so that society can finally be free from the burden of this terrible disease.

All things considered, shouldn't blocking telomere lengthening be a majority concern in the cancer research community? Why is that the SENS Research Foundation has to step in to get things done here?

The cancer research community does recognize the blocking of telomere lengthening as an important strategy for the treatment of cancer. The problem is that since the telomerase-based pathway is used by about 85% of all cancers, most of the community is concerned with therapeutic approaches aimed at disrupting telomerase-expressing cancer cells through a variety of methods. Thus it is not surprising that a lot of these approaches are already in advanced stages of clinical trials. On the other hand, ALT-specific anticancer therapies simply do not exist outside the realm of basic scientific research. This is why the SENS Research Foundation stepped in to bridge this gap by developing technologies that can advance the field of ALT cancer research as quickly as possible. Since the ALT mechanism is used by 15% of all cancers, any telomerase-based therapeutic approach would be ineffective for these patients, so there is a significant unmet clinical need here that definitely deserves more attention from the cancer research community, public and private alike. Moreover, there is an increasing amount of evidence suggesting that attacking telomerase-expressing cancers will lead to some of them switching to the ALT mechanism, rendering the antitelomerase therapy useless against the disease at that point. The SENS Research Foundation and our group in particular are working really hard to give cancer patients better treatment options that can potentially cure the disease or significantly improve its prognosis.

Most of us have no idea what a day's work in a molecular biology lab looks like. What sort of projects do you work on from week to week? What are the joys and frustrations?

Working in a lab whose sole purpose is fighting age-related disease in general and cancer in particular is very exciting and rewarding. However, not all of the work we do is the most glamorous since there are a lot of routine procedures needed day to day to keep the lab running smoothly. These include growing cancer cells in different cell culture dishes to generate enough cells to be able to perform many types of experiments, autoclaving all sorts of lab consumables to ensure sterility, washing glassware, and so on. Since our main focus is the high-throughput drug screening project, we are devoting a significant amount of resources towards optimizing our experimental protocols in our robotic liquid handler, the Biomek 2000. Automation is crucial to our work, especially when handling plates that have 384 tiny wells. We also have ongoing collaborations with other labs around the world that rely on our ALT-specific assays to analyze their samples. The incredible feeling of joy we get when a week-long experiment results in positive results that takes us a step closer to a potential life-saving cancer treatment is difficult to describe in words. On the other hand, when a long experiment fails is incredibly frustrating, but we often do learn something new or useful from both successes and failures in the lab. We need the frustrating moments to make the joyful ones that much sweeter!

The world sees cancer research as slow, incremental, and expensive. Can the SENS strategy for cancer treatment help bring an end to that?

I would say that biomedical research as a whole is slow, incremental, and expensive. Cancer research is therefore no exception. There are many factors involved in contributing to this current state of affairs that are well beyond the control of a small non-profit organization like SENS Research Foundation. Nonetheless, our technologies can potentially accelerate the pace of discovery in the field of ALT cancer research by allowing scientists to screen thousands of small molecules from a variety of libraries to pinpoint genes, RNA entities and drugs that are involved in the regulation of ALT activity. Such discoveries, combined with the advancements made in telomerase cancer research, can lead to a more dynamic pace of therapeutic development to address the societal burden of virtually all known cancer types. Our high-throughput research tools should also lower the cost of cancer research by reducing the time needed to identify potential candidates through complete automation of the procedure as well as by lowering the amount of reagents needed to run the assays.

If you were made benevolent ruler of the cancer research community today, how would you improve the present state of affairs?

I would donate a million to our crowdfunding campaign at! All joking aside, I do encourage everyone to contribute to our campaign since every single donation counts and gets us closer to a potential life-saving treatments to ALT cancer patients. As a benevolent ruler of the cancer research community I would divert more resources to the development of therapies for cancers that currently have the lowest long-term survival rates, such as brain cancer. Incidentally, about 15% of cancers in the central nervous system are positive for ALT activity. As with most cancers, the prevalence and death rates from brain cancer increase sharply with age, but this type of cancer is also the second most common among children. I am very excited about the prospect of changing a brain cancer diagnosis from a de facto death sentence to a treatable disease with long-term patient survival outcomes. Another decree as the community ruler would be to investigate in more detail the potentia l of combining different therapeutics to treat several types of cancer. In our case, we believe that the combination of telomerase and ALT inhibitors will potentially treat any type of cancer by completely hampering the ability of cancer cells to generate new telomeric DNA sequences at the ends of their chromosomes. This in turn will prevent cancer growth and dramatically improve patient outcomes. But even this combinatorial treatment could be boosted by adding another drug that inhibits a different molecular pathway involved in the growth of several types of cancer, such as the signaling pathways regulated by Ras genes.