Shasqi (YC W15) aims to make chemotherapy more powerful and less toxic
forbes.com
forbes.com
More info can be found here:
https://blog.ycombinator.com/shasqi-first-in-human-clinical-...
My girlfriend had breast cancer twice already, and actually I was quite scared that she told me that she would almost rather die thank go through chemotherapy again, it was so bad for her (she's been through more than 15 operations, but she doesn't care about that). Currently it looks that she can't ever stop taking anti-estrogen drugs ever in her life even though it has lots of side effects.
My question is: most of the drugs fail at one of the trials with much more than 90% probability. What is the chance you give your drug to be succeeding, and how did you get failure rate probability under that 90%? Also what's plan B?
In our particular case, we took a known chemotherapeutic agent called doxorubicin. It has been used for the last 40 years in about a dozen types of tumors (include certain types of breast cancer).
The problem is that 3 out of every 4 patients end up major side effects to their immune system (e.g. neutropenia), but even worse, you can only take about 6 doses in your whole life, otherwise your risk for cardiac damage increases very rapidly. It is known colloquially as red death and red devil, because of its red color.
Using that drug as the starting block for our approach improves our probability of success and helps us know what to expect in terms of side effects.
After new extremely complicated surgeries where most surgeons said that it's impossible to get the tumor out of her body (there was only 1 surgeon who took the chance), now she's back on anti-estrogene therapy and it seems that she can't ever stop it again in her life, or at least until some better therapy is available.
I'm quite hopeful of the liquid cancer biopsies though, detecting the small amount of early stage cancer DNA inside the blood will get useful as the thoughput of DNA sequencing increases exponentally, but the cancer curing trials look promising as well.
With regards to your point about liquid biopsies.
To have a minimally invasive sensitive and specific test would be a great addition to the toolbox against cancer. However, if it comes back positive, then what comes next? Maybe surgery? But if we had therapies that were highly effective and could concentrate the cancer drug at the tumor with minimal side effects that may be preferential or supportive to going through the operating room, anesthesia and necessary morbidity of surgery. And potentially you could do this multiple times if needed.
The reason why I'm more hopeful about liquid biopsies than greatly improved cures at this point is because it depends on an informational technology that is relatively predictable, and has a high chance of success for many types of cancer at the same time. Testing has 0 side effects, and can be done for $2000/year in a few years, as the providers are not planning to go through insurance companies first. Also it can be launched globally as long as the blood withdraval can be taken care of.
Shasqi's goal sounds amazing, but it needs to go through all the clinical trials, it has to be covered by health insurance, which takes much more administration work, it has a 10% chance of success for the first time (as it's in stage 1 trial right now), and will take at least about 5-10 years to succeed for just 1 type of cancer, even if it's an extremely important type.
> CEO Dr. José M. Mejía Oneto, who has a PhD in organic chemistry and trained as a medical doctor
As an electronics PhD student with a growing interest in medical applications of my skills, how does one go about training as a medical doctor? Are there shortcuts one can take if not intending to practice? Though at this point, it seems to me that recognition/credentials is a bit orthogonal to building up knowledge.
There are also various 1-2 year MS degree programs, often called "MS in biomedical sciences", which can function as a bridge into medical careers. Some are designed to prepare for MD or other professional school, while others have a focus on broader background (variety of subjects like anatomy, physiology, and pharmacology).
Another option is to learn on the side, and ask actual doctors to confirm/infirm theories and assess feasibility, but without credentials, it's easy to get dismissed...
A quick google search shows that Dr. José M. Mejía Oneto went to the University of Minnesota and did their residency at UC Davis. All this was done after their PhD in Chemistry from Emory.
I don't know if there's any other way to get medical training that will give you any level of authority or respect other than medical school (or related profession like PA or Nurse)
This one talks about the effect of our therapy on local and distant tumors:
https://www.biorxiv.org/content/10.1101/2020.10.13.337899v1
This other one talks about the potential applications of the CAPAC platform and the versatility of our chemistry approach:
Ive been out of touch in this, could you clarify what is the current scientific consensus on the role of immune responses in chemotherapy efficacy vs. direct killing? How does your approach fit into that model?
Further,Could you comment on the immunogenicity of the tumor model you used to test the drug? It's a cell line from the same strain but it's still a line with probably a ton of mutations. Have to tried to establish tumors with more benign cells (or spontaneous tumor models ) to see if the efficacy can be matched in such scenarios as well?
On chemo leading to cytotoxic vs immune killing I am not sure that we have reached the point of a consensus on this. I would say that there is more and more evidence of the involvement of the immune system even with therapies that were considered exclusively chemotherapies. I would suggest looking up the work of Guido Kroemer on immunogenic cell death.
On the CAPAC approach fitting that model Well, our inclination is that our current knowledge is limited by what can be achieved with our current dosing technologies.
For instance, in the specific case of Doxorubicin, you cannot give more than 75 mg/m2 without significantly endangering a person’s health. Assume that only 1-2% of that dose actually reaches the tumor. How would you know what 10x that dose at the tumor would do? Also how could you separate the effect on the tumor and the side effects that it causes? About 20-30 years ago, investigators were experimenting with increasing the dose by 20-30% by providing highly risky interventions such as bone marrow transplant. Not surprisingly those studies showed that the toxicity from the drugs was leading to deaths more quickly than the actual disease, so the efforts were abandoned. We believe that the CAPAC technology allows one to explore biological effects, including a potential activation of the immune system that we have not been able to explore yet. And that is only talking about a single chemotherapy. Imagine if you could have at your disposal many cancer drugs with different mechanisms of action all working at the tumor site at the same time. The effects could be revolutionary.
With regards to the tumor model We have used different syngeneic lines (fast growing, slow growing) and they all point in the same direction. We have not tried yet spontaneous tumor models.
By the way, the efficacy is not matched with that of conventional doxorubicin. The efficacy is surpassed with fewer side effects.
I have a question, but it is more of an advice one, rather than specifics about your company. I am going to soon embark in a Masters program for medical research, then medical school after. What advice do you have for a novice that is interested in the idea of starting a biotech company in the future? What are the things I can do now that can set me up for the future with regards to starting a biotech company?
https://www.basicbooks.com/titles/azra-raza/the-first-cell/9...
“Here’s how Shasqi’s treatment works: Say a patient has a tumor in her breast. The first step is to inject a biopolymer—naturally occurring molecules—into the tumor that essentially function as a magnet. Next, the patient will receive a modified version of the chemotherapy drug doxorubicin, which has been chemically “switched off” so that it’s about 80 times less toxic. But once the drug gets to the tumor site, the biopolymer “magnet” pulls the drug in, causing a chemical reaction that switches the drug on to its full effect. The end result? Higher doses with fewer side effects (or at least that’s what Shasqi is hoping the clinical trial will bear out.)“
Our goal is to enable the same response in others who may experience side effects and may have to forgo treatment because of it.
Doxorubicin, also nicknamed red devil or red death, is notorious for its side effects. In addition to the bone marrow toxicity common to most chemotherapies, a person cannot receive more than 6 doses of doxorubicin in their lifetime without increasing their risk of heart failure. So when patients respond to doxorubicin, but more doses are needed, the patient and the doctors face a difficult choice: risk of death from the cancer or risk of cardiac failure. Shasqi is trying to change that equation for solid tumors. We are not focused on lymphomas yet.
But the description from this article suggests they're trying to make the chemo more targeted to the site of the tumor. That seems to counteract what I had understood to be the point of chemo.
Can you explain? (In case it wasn't obvious from the above, I have low knowledge in this area.)
Chemo is effectively a poison that poisons the tumour faster than the rest of the body; the tumour’s cells are more susceptible to the poison than normal cells because they’re reproducing faster. As such, it doesn’t matter whether the tumour is large or small, localised or metastatic. It’s given systemically simply because of the nature of the drugs in question - because that’s generally how we get drugs into the body. Local administration of drugs is rare, and chemo especially so.
I haven’t read the article, but if you can integrate this with regular chemo cadence to amplify effects at certain locations it seems like a no brainer.
Your technology requires localised injection of the biopolymer ‘magnet’. Is the injection intratumoral? How difficult/specialised is this technique, and to what extent do you expect subtle differences here might influence the efficacy?
There has been a recent wave of intratumoral approaches particularly for immunooncology (e.g. TLR, Sting, oncolytic viruses) and there are manuscripts in the scientific literature about the technical challenges and possibilities (https://jamanetwork.com/journals/jamanetworkopen/fullarticle...).
So, to your question, yes it is specialized, but not particularly difficult. We have taken great care to leverage the learnings of those experts to minimize the challenges of interpatient variability.
But we will only know for sure if our efforts where sufficient once the human clinical data comes back. For now I can say that our preclinical studies are highly encouraging.
dumb question: if you can inject the biopolymer directly into the tumor, why can't you inject doxorubicin directly into the tumor?
In your one paper you test Doxorubicin, where the site of action is the tumor DNA itself. Presumably the biopolymer remains extracellular, so how does the "bound" Doxorubicin get to its active site?
Do you see Doxorubicin "unbinding" over time? Does the biopolymer itself enter the cell through phagocytosis?
Our approach increases the extracellular concentration of Dox and then it does the same job that it usually does.
To me it seems like one upside of using a well known chemo agent is that the oncology community is going to be familiar with it and possibly more receptive to adopting it into their practice. Probably will help with the approval process too.
Is the delivery method a major aspect of the trial? Could the biopolymer be adjusted to also provide embolization and/or doped on some of the materials used for Y90/SIRSphere type targeted radiotherapy?
This really seems like a cool idea, I wish you and your team the best!
Nothing special about doxorubicin. This is a broad technology that can be applied to many cancer therapies, including radionuclides as you as asked.
I agree with your comments on using a known agent.
We have an investigational product, which means it can only be used in the context of a clinical trial.
All products that eventually reach the clinic have to go through this step and rigorous testing before being available to physicians and patients.