The MMTP Staff took opportunity to catch up with SENS Research Foundations Dr.Haroldo Silva who is leading the OncoSENS campaign seeking cures for ALT Cancer. Before we get into the interview it is worth reading the summary from Lifespan.io about what ALT cancer is, how it works and why it is critical to support research that seeks to find solutions for treatment. Remember this research is all funded by donations and progress relies on everyone supporting this work so please make a donation today.
Every time a normal somatic 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 enters senescence or undergoes apoptosis (programmed cell death). Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Most cancer cells bypass this failsafe by synthesizing new telomeres using the enzyme telomerase.
Several therapies targeting this well-described telomerase-based pathway are in the advanced stages of clinical development, but as with any cancer therapy there is the potential for development of resistance against telomerase-based strategies to defeat cancer. Studies using mice and human cancer cell lines have demonstrated that cancer can overcome the loss of telomerase by using a telomerase-independent mechanism called alternative lengthening of telomeres (ALT). Furthermore, existing tumor cells in mice have also been observed to switch over to the ALT pathway as a result of telomerase-inhibiting treatment. It is therefore plausible that telomerase-dependent cancer treatments will introduce selective pressures in human tumors to activate the ALT pathway and/or select for cells already using ALT within the tumor. This makes the development of ALT-specific therapies imperative for the success of complete anti-cancer approaches.
There are currently no ALT-targeted anti-cancer therapeutics, however, largely because this process is much less well understood. In contrast to telomerase-driven telomere lengthening, which does occur in the stem cells of healthy tissues and organs, ALT activity is not found in normal human postnatal tissues. A positive side of this fact is that this would allow for more-effective dosing with minimal side effects. ALT is present in some of the most clinically challenging cancers to treat, such as pediatric and adult brain cancers, soft tissue sarcoma, osteosarcoma, and lung cancers. Clearly, targeting ALT is a very attractive strategy in the development of novel cancer therapies.
1. I saw the article “Control ALT, Delete Cancer” about this project that you co-wrote in April, 2015. Why are you only now starting the crowdfunding effort?
Because we are now at the point where our hard work paid off and we were able to overcome most of the technical hurdles associated with making our novel ALT-specific assay compatible with robotic/automation methods. This is essential to performing high-throughput and large-scale screening studies.
2. What will you be looking for in your screening process as an indication that a given compound has potential to prevent ALT-based cancers?
We will be measuring a particular biomarker that has only been observed in ALT cancers, namely C-circles, which are circular pieces of DNA containing a repetitive sequence only found at the ends of chromosomes (i.e., telomeres). This biomarker was discovered by our collaborator, Dr. Jeremy Henson, about 7 years ago and it is the most closely correlated with ALT cancer activity. The more ALT activity is present in a given cancer, the higher the levels of C-circles present in them. Therefore, once we exposed the ALT cancer cells to different compounds we will measure C-circle content quickly to assess if any of the compounds was able to inhibit the ALT pathway.
3. You mentioned that if you raise $200,000, you could screen 115,000 compounds. However, the crowdfunding goal is only $60,000 – how many compounds will you be able to screen for $60,000?
We should be able to screen about 35,000 compounds, which is already an unprecedented number in the field of ALT cancer research. We will also prioritize our screen by first looking at all compounds currently approved for use in patients as well as drugs that were tested in clinical trial and were deemed to be safe. These compounds, if found effective against ALT cancers, can be more quickly repurposed for development into an ALT cancer-specific therapy.
4. Will you be using the C-circle assay mentioned in the above article to perform your screening?
Yes, we will. See answer above (question 2).
5. If your screening does find a promising compound, what do you plan to do with it? Will you patent its anti-ALT properties?
After exhaustive validation of the initial positive screening results, the next step will depend on the nature of the particular compound. If it is currently used in patients for cancer or any other indications we could approach the company that commercializes it to start a joint development program focused on ALT cancer therapy. Otherwise we will explore alternative ways of moving the development of these potential therapies into the private sector. We will absolute aim to patent any compounds that we find helpful in the fight against cancer whenever possible.
6. If your screening does find a promising compound, when would it be available to ALT-based cancer patients?
It takes an average of 12 years for a compound to go from discovery to clinical use in the US. Now, it is possible to reduce that time significantly in case the promising compound we find in our screening is either already approved for clinical use or has been through extensive clinical trials. We will be testing such compounds as part of our screening as explained above. Alternatively, we could target initially ALT cancers that affect less than 200,000 patients in the US in order to obtain orphan drug designation, which can significantly expedite the approval process. This would pave the way for bringing therapies to more common ALT cancers.
7. How many other groups have also looked at ways to inhibit ALT?
There are very few research groups performing ALT-related cancer research worldwide, especially when you compare it to the amount of scientific output from telomerase-based cancer research efforts. Even within the research groups dedicating a lot of resources to ALT research, none of them to the best of our knowledge have the technical capability to perform such a large small molecule screening in the way we are planning to do it. Our technological achievement with the C-circle assay puts our group in a unique position to perform the largest screening study ever attempted in the field of ALT cancer research.
8. How many researchers will be involved in OncoSENS?
There will be two research groups working full time on this project. One group is in Australia at the University of New South Wales (UNSW) and headed by Dr. Jeremy Henson while our group is based in Mountain View, CA at the SENS Research Foundation. Most of the screening process will take place at UNSW at their state-of-the-art facility dedicated to automation and large-scale robotic applications in cancer research.
9. Could you provide a rough break-down on what the funds raised through crowdfunding would be spent on?
This information can be found at https://www.lifespan.io/campaigns/sens-control-alt-delete-cancer/.
10. Why do you need to crowdfund at all? Didn’t SENS just get a $10 million donation? And hasn’t Peter Thiel been giving SENS a million a year for a while now?
We are really grateful to both Peter Thiel and Michael Greve for their generous support of our research efforts as an organization. However, we are a small non-profit organization with very ambitious long-term goals, namely the eradication of all age-related disease from society. That will take a lot more investment to solve. Half of Greve's $10 million commitment to addressing the diseases and disabilities of aging will go to Project|21, which is our largest fundraising effort yet ($50 million goal). The other half will go exclusively to seed investments in startups focused on making rejuvenation biotechnologies a reality.
The goal of our crowdfunding campaign goes beyond simply obtaining the resources we need to start screening a massive drug library for potential ALT cancer therapies. It will also raise awareness of the specific projects supported by SENS Research Foundation while simultaneously getting the public at large engaged in the fight against age-related diseases. Most people of course cannot contribute at the level of Thiel or Greve, but I keep emphasizing that every single dollar we raise counts in our fight against aging in general and cancer in particular. Our campaign allows everyone to do exactly that by contributing any amount they can spare, giving all a chance to participate in defeating aging!
11. Could you have applied for an NIH grant? Given that NIH provides $6 billion to cancer research every year.
Actually, NIH funding for cancer research has been relatively flat in recent years and adjusted for inflation funding levels are the same as they back in the late 90's. There is tremendous competition for NIH funds from well-established research institutions nationwide. We hope that our campaign will be successful in raising the funds we need to demonstrate that our technology works and place us in a much better position to write a grant to the NIH in the near future, but we are not quite there yet. This is another reason to learn, donate and support our work at Lifespan.io and the OncoSENS Campaign.
12. Are you actual SENS Research Foundation employees?
Yes we are, except for our collaborators in Australia.