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Scholar Spotlight: Haroldo Silva is Working Toward a Universal Cancer Therapy

ARTICLE BY: Corrie Goldman

Siebel Scholars Foundation

July 8th 2016

Aging is a fact of life, and for many people, about 39,000 every day globally, a cancer diagnosis will come with advanced age. Unfortunately, that will also mean a death sentence for many patients as more than 22,000 people die of cancer daily around the globe.  But Siebel Scholar Haroldo Silva (UC Berkeley, BioE ‘11) is working to change that.

Silva is a research scientist at the SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease.

Since 2013, Haroldo has led a project at SRF that aims to treat and prevent cancers that rely on a process known as Alternative Lengthening of Telomeres (ALT). The ALT mechanism is present in 10-15% of all cancers, including some of the most clinically challenging cancers to treat, such as pediatric and adult brain cancers, soft tissue sarcoma, osteosarcoma, and lung cancers.

Every time a healthy cell divides, the DNA at the ends of its chromosomes, called telomeres, gets shorter. When the telomeres shorten too much, the cell permanently stops dividing and either remains dormant or dies. Telomere shortening acts as a natural biological mechanism for limiting cellular life span, but virtually all types of cancer cells bypass this process, allowing them to replicate indefinitely until they impair healthy tissue and organ function.

A “universal” cancer treatment absolutely needs to address the two ways by which cancer cells lengthen and maintain their telomeres: i.e., they either express an enzyme called telomerase or they switch on ALT. The ALT process enables cancer cells to continue to elongate their telomeres, but without telomerase. The exact mechanism by which this occurs is not well understood by scientists, but a reliable biomarker that clearly indicates when ALT is happening was discovered by Silva's collaborator, Dr. Jeremy Henson, back in 2009.

In the war against cancer, there are several anti-telomerase therapies in advanced stages of clinical development, but nothing currently exists that is capable of specifically targeting ALT.

Silva’s current research project “Control ALT Delete Cancer” aims to find drugs that specifically shut down the ALT pathway, therefore preventing cancer growth and paving the way toward the first ever ALT-specific anticancer therapeutics.

The goal of the project is to screen a library of about 115,000 compounds containing structurally diverse, medicinally active, and cell permeable drugs already in use across a variety of fields of medicine (oncology, cardiology, and immunology, etc.), for potential inhibitors of the ALT pathway.

There are two crucial advantages to using such a diverse drug library: (1) it greatly increases our chances of identifying any drugs capable of hampering the ALT mechanism and (2) the library of drugs to be screened includes previously FDA-approved compounds, which can potentially be repurposed for the treatment of patients with ALT cancers through cheaper, faster and safer preclinical and clinical validation protocols.

Because SRF is a small non-profit organization, they have launched a crowdfunding campaign to help support Silva’s work. The $60,000 goal will help support Silva’s team as they work on this project and towards the larger mission of freeing humanity from the burden of cancer.

Silva spoke with the Siebel Scholars program about his work.

Q: You were drawn to working at SENS Research Foundation after you heard its founder (Aubrey de Grey) give a talk while you were a grad student at Berkeley. What was it about the SENS approach to combating the diseases of aging that piqued your interest?

The SENS approach is composed of seven different strands of research encompassing all known types of damage that accumulate inside our bodies as we age. Aubrey calls them the ‘seven deadly sins’. Cancer is of course one of most deadly sins as the second biggest killer in the US. The SENS approach to combat age-related diseases provides an actionable blueprint to scientifically tackle all of the molecular and cellular damage that is slowly killing all of us as we get older.

Q: What does a typical day on the job look like for you?

Well, 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, general equipment maintenance, etc. We also spend a lot of time performing data analyses on the computer as well as planning and implementing new experiments.  And we have our own robot.

Q: What would you say is the biggest benefit of doing research for a non-profit organization?

The biggest benefit of doing research at SRF is the freedom we have to conduct our research in the best way we see fit by deploying our limited resources into the projects we believe have the best chance in addressing the disabilities and diseases of aging.

Q: And what’s the biggest challenge?

The single biggest challenge is finding generous donors willing to support our work so that we can keep fighting the battle against age-related diseases. In our particular case, this often requires a paradigm shift in the thinking of most people who do not actually see aging as a problem due to various religious, philosophic or socioeconomic reasons.

Q: What is it about ALT that makes it such an attractive strategy in the development of novel cancer therapies?

One of the main drawbacks with current anticancer approaches is that chemotherapy kills both healthy and cancer cells (i.e. lack of specificity). ALT is a process that has never been observed in normal human tissues, which means that if we can find a drug that specifically targets the ALT mechanism, it should not have any side-effects while stopping cancer growth.

Q: Currently there are no ALT-targeted therapeutics because the process is not well understood. What about the process makes it so difficult to study?

The main challenges in ALT research are identification of a biomarker that can reliably tell us the amount of ALT activity happening inside a cancer cell and development of a robust method to test this biomarker in high-throughput screens. In 2009, our collaborator Dr. Jeremy Henson solved the former by discovering such a biomarker and named it C-circle. Now we have solved the latter issue by developing an assay for C-circles that is fast and fully compatible with automation to allow rapid testing of thousands of compounds.  This is why we are so eager to get the funding we need.  We are in a unique position to begin screening 115,000 drugs this year, which is unprecedented in the field of ALT cancer research.

Q: Why is the development of ALT-specific therapies imperative for the success of complete anti-cancer approaches?

Since virtually all cancers rely on either ALT or telomerase for telomere maintenance, shutting down both mechanisms is an attractive strategy for a universal cancer therapy. However, ALT research is years behind relative to the progress observed in telomerase-based anticancer research. Our ‘Control ALT Delete Cancer’ campaign aims to bridge this gap by vastly accelerating the pace of drug discovery in the ALT cancer research field.

Q: What happens if you identify a drug that seems promising in terms of stifling the ALT process?

We would need to do a lot of additional testing of this drug to validate this initial finding. Such testing includes generating a complete profile of effective dosage response, drug toxicity, cell growth analyses, mechanism(s) of action, etc on a panel of different ALT, telomerase and mortal human cell lines. But the long-term goal is to get the drug to patients after successful clinical trials. In other words, we will help people strike back against some of the worst kinds of cancer including pediatric and adult brain, lung and soft tissue cancers.

Q: How do you respond when people ask you if you’re going to cure cancer?

I like to remind people that advancements in prevention, diagnostics and cell biology have already essentially cured several cancers. For instance, breast cancer has a 91% 5-year survival rate while brain and other central nervous system cancers, which incidentally have a high prevalence of ALT, have only a 35% 5-year survival rate. So what I say is please support us in our efforts to make our world a better place by getting rid of all the cancers we have not cured yet. You can learn more about our work and donate at www.lifespan.io/campaigns/sens-control-alt-delete-cancer/ or www.sens.org.

Siebel Scholars can connect with Silva by logging into our Community Website.