7 ms·

Shasqi (YC W15) aims to make chemotherapy more powerful and less toxic

138 points by mejiaoneto 6y ago

mejiaoneto 6y ago
This is Jose, CEO of Shasqi. There are three firsts that Shasqi announced this morning: 1. First time click chemistry is used in humans. 2. First YC company to reach first-in-human clinical trials 3. First two patients dosed for SQ3370 in Shasqi's Phase 1 clinical trial More info can be found here: https://www.shasqi.com/ https://www.shasqi.com/ https://blog.ycombinator.com/shasqi-first-in-human-clinical-trials/ https://blog.ycombinator.com/shasqi-first-in-human-clinical-... https://en.wikipedia.org/wiki/Click_chemistry https://en.wikipedia.org/wiki/Click_chemistry
- MayeulC 6y ago
  Congratulations, reaching that stage is very impressive and could be life-changing to a lot of people. > 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.
  - RandallBrown 6y ago
    As far as I understand, that means they went to medical school. 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)
    - an_opabinia 6y ago
      Maybe Dr Oneto can clarify but it does not appear he completed his surgery residency. This is not super material with respect to what he is doing now, but I believe this is why such unusual phrasing is used in the article. It is likely Dr Oneto still passed his medicine boards and is a licensed MD, he just is limited to taking care of post surgical patients (moonlighting) and is not able to perform surgeries in California.
  - mejiaoneto 6y ago
    That is an interesting question. Thank you for sharing. Indeed, I was a chemistry PhD before going to medical school. Unfortunately, there are no easy shortcuts that I know of. Interestingly it is a bit unpredictable if somebody will practice medicine or not when they go to do an MD or MD/PhD.
    - MayeulC 6y ago
      Thank you for your answer. After nine-ish years of higher education, I'm not sure I want to double down on that. Not right away, at least. 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...
  - ihnorton 6y ago
    If you are interested in medical devices, at least in the US there are hospital-based postdoc positions which will hire some engineering PhDs even w/out specifically medical thesis focus (as you are coming from ferroelectrics: potentially MRI or robotics research). In such a position there is a lot of opportunity to attend medical lectures, and also ideally to shadow MDs in clinic, observe procedures, and sit in on case reviews. 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).
- xiphias2 6y ago
  Hi Jose, thanks very much for working on this! 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?
  - mejiaoneto 6y ago
    Sorry to hear about your girlfriend. I have heard those feelings as well. They are not uncommon. The probability of success changes as you move further in the development. Below there is a link for a booklet that talks about the general pharma odds in page 53. 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.
  - AnthonBerg 6y ago
    I’m sorry. We’ve been through breast cancer and anti-estrogen therapy. It’s hard.
    - xiphias2 6y ago
      The problem with my girlfriend is that she thought she went through it, but after 4 years she stopped anti-estrogen therapy because she wanted a baby, and 1 year later her breast cancer got metastatic. 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.
- mejiaoneto 6y ago
  In addition, for those who are interested in learning more, here are two pre-print manuscripts that we submitted this week. 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 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: https://doi.org/10.26434/chemrxiv.13087715.v1 https://doi.org/10.26434/chemrxiv.13087715.v1
  - ramraj07 6y ago
    Great work. My money is still on the wall on whether localized chemotherapy will be as/more effectivr, but you've been as systematic as can be and it's worth a shot to test in humans. Glad you used syngenic models instead of xenografts. 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?
    - mejiaoneto 6y ago
      Thank you for your comments. With regards to your questions. 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.
- srckinase123 6y ago
  Hello Jose, I wish you success in such an important endeavor. 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?
  - mejiaoneto 6y ago
    I am not sure that there is any one path or unique suggestion. But my general advice was to stay curious, learn as much as possible and keep an eye for what could be, rather than just accepting things as they are. Also I strongly believe in the cross pollination of concepts leading to unique ideas. So having some sort of orthogonal knowledge in addition to medicine is helpful (e.g. business, chemistry, biology, programming, etc).
- nradov 6y ago
  Have you read "The First Cell" by Dr. Azra Raza? What do you think of her criticism of current approaches to cancer treatment? https://www.basicbooks.com/titles/azra-raza/the-first-cell/9781541699526/ https://www.basicbooks.com/titles/azra-raza/the-first-cell/9...
  - mejiaoneto 6y ago
    Thank you for sharing. The book looks interesting, but I have not read it yet, so I cannot comment.
- deleted 6y ago
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- gogopuppygogo 6y ago
  I also know firsthand how difficult it is to do a human health startup. Thank you so much for sticking with this!
  - mejiaoneto 6y ago
    Thank you. We are very proud of what the team has accomplished and optimistic based on what the CAPAC platform has shown in preclinical studies. The unique aspect of this is that it is based on chemistry not biology so it seems that the reproducibility across species (and hopefully across patients) is better.
- Nelkins 6y ago
  Do you think desmoid tumors roughly fit the profile of cancer types that could be targeted using your technique? https://en.wikipedia.org/wiki/Aggressive_fibromatosis https://en.wikipedia.org/wiki/Aggressive_fibromatosis
  - mejiaoneto 6y ago
    Yes. Any solid tumor that is accesible for an injection and we have reason to suspect it would be sensitive to doxorubicin, would fit the criteria of this phase 1 study. For more info on the clinical trial please visit: https://clinicaltrials.gov/ct2/show/NCT04106492 https://clinicaltrials.gov/ct2/show/NCT04106492
evmar 6y ago
My layman's understanding of chemo is that it's meant to be systemic: surgeries and radiation are targeted at the tumor itself, while chemo is meant to hopefully wipe out cells that have reached other parts of the body. 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.)
- rubatuga 6y ago
  Chemo can be both curative or palliative. This means it can be used to cure the cancer, or simply prolong the life of a patient. Chemo can also be used in combination with surgical or used alone. Just because chemo affects most dividing cells doesn’t mean it is not a curative treatment. Targeted chemo therapies have less side effects and can be tolerated at higher doses.
  - evmar 6y ago
    I think all of the things you just wrote are true, but I don't see how they answer the question I asked... ?
    - mejiaoneto 6y ago
      1. Cancer is characterized as local tumor, locoregional or distant (metastasis). 2. Our approach can certainly help patients with local or locoregional disease. 3. As we have presented in multiple cancer conferences, our approach seems to also help with distant disease, because by focusing more powerful therapy to the tumor, sparing the rest of your body, we give the body the opportunity to recognize the tumor as foreign and fight it. https://cancerres.aacrjournals.org/content/80/16_Supplement/6245 https://cancerres.aacrjournals.org/content/80/16_Supplement/... https://www.biorxiv.org/content/10.1101/2020.10.13.337899v1 https://www.biorxiv.org/content/10.1101/2020.10.13.337899v1
- tomerico 6y ago
  It's not uncommon to use chemo treatment to shrink the growth prior to removal.
mft_ 6y ago
Interesting - congratulations for making it into phase I. 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?
- mejiaoneto 6y ago
  Thank you for your thoughts and question. 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/2768765 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.
  - mft_ 6y ago
    Thanks for your comprehensive reply - and the very best of luck to you and your team!
cogburnd02 6y ago
For a moment--just reading the title--I thought this had something to do with 'Shaq' O'Neill.
mmaunder 6y ago
I’ve been on Doxy and it nuked what I had, and as a patient I’d be extremely nervous about detoxifying the badass chemical that’s supposed to kill the thing that was killing me. The side effects weren’t bad enough for me to want to make it less potent. Also worth noting that it sounds like it wouldn’t work for something diffuse like B cell non-hodgkins lymphoma. “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.)“
- maxander 6y ago
  Presumably, making it more targeted means they can use more, potentially to the point that the effect on the tumor would correspond to a lethal systemic dose using a course of normal doxorubicin. The patient wouldn’t feel any better while undergoing the therapy in that case, but worse tumors could be successfully treated. The effect/toxicity ratio is the key factor in a lot of these kinds of drugs.
  - mejiaoneto 6y ago
    That is absolutely right. By honing the drug to the tumor, and minimizing the effects on the rest of the body, you are essentially able to unlock power on the tumor that would have put the patient's life at risk before. Taken it even a step further, if you have a system that selectively gets the drug to the tumor, then you can give combinations of cancer drugs that would be otherwise lethal, also preventing the possibility of mutations that would make the tumor unaffected by a single drug. The possibilities are immense.
- mejiaoneto 6y ago
  Thank you for your comment. Congratulations on your positive response and recovery. 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.
panabee 6y ago
thanks very much for working on this. dumb question: if you can inject the biopolymer directly into the tumor, why can't you inject doxorubicin directly into the tumor?
- mejiaoneto 6y ago
  The CAPAC technology allows you to give multiple daily doses of the therapy for 5 consecutive days after injecting the tumor with the biopolymer once. This is a significant advantage to needing to inject the tumor daily.
  - panabee 6y ago
    thanks for the response. this is awesome work you're conducting. if you can inject directly into the tumor, why not do a high enough dosage to kill the tumor in one shot?
    - mejiaoneto 6y ago
      Because this cannot be achieved with one dose. Also think about diffusion in tissue of small molecules. Essentially within an hour or two, anything that you injected in the tumor is gone. So now you are asking about killing everything with a drug in a specific part of the body within one hour without much damage to the rest of the body... It does not sound that easy anymore and that is probably why people resort to surgery, in other words remove the diseased tissue. The problem is that it is often hard to make sure you have removed all of the diseased tissue and you have “clean margins” and none of those cells have already infiltrated areas of the body where you could not detect them. In other words, a pretty challenging problem. Having another tool available to fight this disease would be significantly beneficial.
charliebrownau 6y ago
Ever considered to walk away from mainstream and cehmo and instead look at real solutions using Diet, Hemp/weed, Juicing,etc
deleted 6y ago
[deleted]
refurb 6y ago
I haven't dug into your papers to a great extent, but off the top of my head - you're injecting a biopolymer, followed by a modified chemotherapeutic agent. The chemotherapeutic agent then binds to the biopolymer. 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?
- mejiaoneto 6y ago
  Thank you for your comment. Our approach increases the extracellular concentration of Dox and then it does the same job that it usually does.
  - jcims 6y ago
    Are there general strategies for adapting drugs to click-chemistry or is there something special about doxil that makes it amenable to this approach? 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!
    - mejiaoneto 6y ago
      Thank you for your wishes. 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.
  - refurb 6y ago
    Do you know the mechanism? Retro-Diels Alder?
notananthem 6y ago
Anyone have any issues with the messaging for a medical product with no proven success? "Use our product because the other option is poison!! Also we're only in phase one!!!"
- mejiaoneto 6y ago
  Thank you for your comment. 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.
faumleite 6y ago
That’s amazing! I’m an oncology pharmacist and Think that will improve the patient treatment, and also makes possible to use the chemotherapy To groups that’s used not To Be possible the use. I’ll keep my eye In this technology!

138 points by mejiaoneto 6y ago

This is Jose, CEO of Shasqi. There are three firsts that Shasqi announced this morning: 1. First time click chemistry is used in humans. 2. First YC company to reach first-in-human clinical trials 3. First two patients dosed for SQ3370 in Shasqi's Phase 1 clinical trial More info can be found here: https://www.shasqi.com/ https://www.shasqi.com/ https://blog.ycombinator.com/shasqi-first-in-human-clinical-trials/ https://blog.ycombinator.com/shasqi-first-in-human-clinical-... https://en.wikipedia.org/wiki/Click_chemistry https://en.wikipedia.org/wiki/Click_chemistry

MayeulC 6y ago
Congratulations, reaching that stage is very impressive and could be life-changing to a lot of people. > 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.
- RandallBrown 6y ago
  As far as I understand, that means they went to medical school. 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)
  - an_opabinia 6y ago
    Maybe Dr Oneto can clarify but it does not appear he completed his surgery residency. This is not super material with respect to what he is doing now, but I believe this is why such unusual phrasing is used in the article. It is likely Dr Oneto still passed his medicine boards and is a licensed MD, he just is limited to taking care of post surgical patients (moonlighting) and is not able to perform surgeries in California.
- mejiaoneto 6y ago
  That is an interesting question. Thank you for sharing. Indeed, I was a chemistry PhD before going to medical school. Unfortunately, there are no easy shortcuts that I know of. Interestingly it is a bit unpredictable if somebody will practice medicine or not when they go to do an MD or MD/PhD.
  - MayeulC 6y ago
    Thank you for your answer. After nine-ish years of higher education, I'm not sure I want to double down on that. Not right away, at least. 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...
- ihnorton 6y ago
  If you are interested in medical devices, at least in the US there are hospital-based postdoc positions which will hire some engineering PhDs even w/out specifically medical thesis focus (as you are coming from ferroelectrics: potentially MRI or robotics research). In such a position there is a lot of opportunity to attend medical lectures, and also ideally to shadow MDs in clinic, observe procedures, and sit in on case reviews. 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).
xiphias2 6y ago
Hi Jose, thanks very much for working on this! 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?
- mejiaoneto 6y ago
  Sorry to hear about your girlfriend. I have heard those feelings as well. They are not uncommon. The probability of success changes as you move further in the development. Below there is a link for a booklet that talks about the general pharma odds in page 53. 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.
- AnthonBerg 6y ago
  I’m sorry. We’ve been through breast cancer and anti-estrogen therapy. It’s hard.
  - xiphias2 6y ago
    The problem with my girlfriend is that she thought she went through it, but after 4 years she stopped anti-estrogen therapy because she wanted a baby, and 1 year later her breast cancer got metastatic. 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.
mejiaoneto 6y ago
In addition, for those who are interested in learning more, here are two pre-print manuscripts that we submitted this week. 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 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: https://doi.org/10.26434/chemrxiv.13087715.v1 https://doi.org/10.26434/chemrxiv.13087715.v1
- ramraj07 6y ago
  Great work. My money is still on the wall on whether localized chemotherapy will be as/more effectivr, but you've been as systematic as can be and it's worth a shot to test in humans. Glad you used syngenic models instead of xenografts. 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?
  - mejiaoneto 6y ago
    Thank you for your comments. With regards to your questions. 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.
srckinase123 6y ago
Hello Jose, I wish you success in such an important endeavor. 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?
- mejiaoneto 6y ago
  I am not sure that there is any one path or unique suggestion. But my general advice was to stay curious, learn as much as possible and keep an eye for what could be, rather than just accepting things as they are. Also I strongly believe in the cross pollination of concepts leading to unique ideas. So having some sort of orthogonal knowledge in addition to medicine is helpful (e.g. business, chemistry, biology, programming, etc).
nradov 6y ago
Have you read "The First Cell" by Dr. Azra Raza? What do you think of her criticism of current approaches to cancer treatment? https://www.basicbooks.com/titles/azra-raza/the-first-cell/9781541699526/ https://www.basicbooks.com/titles/azra-raza/the-first-cell/9...
- mejiaoneto 6y ago
  Thank you for sharing. The book looks interesting, but I have not read it yet, so I cannot comment.
deleted 6y ago
[deleted]
gogopuppygogo 6y ago
I also know firsthand how difficult it is to do a human health startup. Thank you so much for sticking with this!
- mejiaoneto 6y ago
  Thank you. We are very proud of what the team has accomplished and optimistic based on what the CAPAC platform has shown in preclinical studies. The unique aspect of this is that it is based on chemistry not biology so it seems that the reproducibility across species (and hopefully across patients) is better.
Nelkins 6y ago
Do you think desmoid tumors roughly fit the profile of cancer types that could be targeted using your technique? https://en.wikipedia.org/wiki/Aggressive_fibromatosis https://en.wikipedia.org/wiki/Aggressive_fibromatosis
- mejiaoneto 6y ago
  Yes. Any solid tumor that is accesible for an injection and we have reason to suspect it would be sensitive to doxorubicin, would fit the criteria of this phase 1 study. For more info on the clinical trial please visit: https://clinicaltrials.gov/ct2/show/NCT04106492 https://clinicaltrials.gov/ct2/show/NCT04106492

evmar 6y ago

My layman's understanding of chemo is that it's meant to be systemic: surgeries and radiation are targeted at the tumor itself, while chemo is meant to hopefully wipe out cells that have reached other parts of the body. 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.)

rubatuga 6y ago
Chemo can be both curative or palliative. This means it can be used to cure the cancer, or simply prolong the life of a patient. Chemo can also be used in combination with surgical or used alone. Just because chemo affects most dividing cells doesn’t mean it is not a curative treatment. Targeted chemo therapies have less side effects and can be tolerated at higher doses.
- evmar 6y ago
  I think all of the things you just wrote are true, but I don't see how they answer the question I asked... ?
  - mejiaoneto 6y ago
    1. Cancer is characterized as local tumor, locoregional or distant (metastasis). 2. Our approach can certainly help patients with local or locoregional disease. 3. As we have presented in multiple cancer conferences, our approach seems to also help with distant disease, because by focusing more powerful therapy to the tumor, sparing the rest of your body, we give the body the opportunity to recognize the tumor as foreign and fight it. https://cancerres.aacrjournals.org/content/80/16_Supplement/6245 https://cancerres.aacrjournals.org/content/80/16_Supplement/... https://www.biorxiv.org/content/10.1101/2020.10.13.337899v1 https://www.biorxiv.org/content/10.1101/2020.10.13.337899v1
tomerico 6y ago
It's not uncommon to use chemo treatment to shrink the growth prior to removal.

mft_ 6y ago

Interesting - congratulations for making it into phase I. 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?

mejiaoneto 6y ago
Thank you for your thoughts and question. 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/2768765 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.
- mft_ 6y ago
  Thanks for your comprehensive reply - and the very best of luck to you and your team!

cogburnd02 6y ago

For a moment--just reading the title--I thought this had something to do with 'Shaq' O'Neill.

mmaunder 6y ago

I’ve been on Doxy and it nuked what I had, and as a patient I’d be extremely nervous about detoxifying the badass chemical that’s supposed to kill the thing that was killing me. The side effects weren’t bad enough for me to want to make it less potent. Also worth noting that it sounds like it wouldn’t work for something diffuse like B cell non-hodgkins lymphoma. “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.)“

maxander 6y ago
Presumably, making it more targeted means they can use more, potentially to the point that the effect on the tumor would correspond to a lethal systemic dose using a course of normal doxorubicin. The patient wouldn’t feel any better while undergoing the therapy in that case, but worse tumors could be successfully treated. The effect/toxicity ratio is the key factor in a lot of these kinds of drugs.
- mejiaoneto 6y ago
  That is absolutely right. By honing the drug to the tumor, and minimizing the effects on the rest of the body, you are essentially able to unlock power on the tumor that would have put the patient's life at risk before. Taken it even a step further, if you have a system that selectively gets the drug to the tumor, then you can give combinations of cancer drugs that would be otherwise lethal, also preventing the possibility of mutations that would make the tumor unaffected by a single drug. The possibilities are immense.
mejiaoneto 6y ago
Thank you for your comment. Congratulations on your positive response and recovery. 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.

panabee 6y ago

thanks very much for working on this. dumb question: if you can inject the biopolymer directly into the tumor, why can't you inject doxorubicin directly into the tumor?

mejiaoneto 6y ago
The CAPAC technology allows you to give multiple daily doses of the therapy for 5 consecutive days after injecting the tumor with the biopolymer once. This is a significant advantage to needing to inject the tumor daily.
- panabee 6y ago
  thanks for the response. this is awesome work you're conducting. if you can inject directly into the tumor, why not do a high enough dosage to kill the tumor in one shot?
  - mejiaoneto 6y ago
    Because this cannot be achieved with one dose. Also think about diffusion in tissue of small molecules. Essentially within an hour or two, anything that you injected in the tumor is gone. So now you are asking about killing everything with a drug in a specific part of the body within one hour without much damage to the rest of the body... It does not sound that easy anymore and that is probably why people resort to surgery, in other words remove the diseased tissue. The problem is that it is often hard to make sure you have removed all of the diseased tissue and you have “clean margins” and none of those cells have already infiltrated areas of the body where you could not detect them. In other words, a pretty challenging problem. Having another tool available to fight this disease would be significantly beneficial.

charliebrownau 6y ago

Ever considered to walk away from mainstream and cehmo and instead look at real solutions using Diet, Hemp/weed, Juicing,etc

deleted 6y ago

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refurb 6y ago

I haven't dug into your papers to a great extent, but off the top of my head - you're injecting a biopolymer, followed by a modified chemotherapeutic agent. The chemotherapeutic agent then binds to the biopolymer. 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?

mejiaoneto 6y ago
Thank you for your comment. Our approach increases the extracellular concentration of Dox and then it does the same job that it usually does.
- jcims 6y ago
  Are there general strategies for adapting drugs to click-chemistry or is there something special about doxil that makes it amenable to this approach? 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!
  - mejiaoneto 6y ago
    Thank you for your wishes. 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.
- refurb 6y ago
  Do you know the mechanism? Retro-Diels Alder?

notananthem 6y ago

Anyone have any issues with the messaging for a medical product with no proven success? "Use our product because the other option is poison!! Also we're only in phase one!!!"

mejiaoneto 6y ago
Thank you for your comment. 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.

faumleite 6y ago

That’s amazing! I’m an oncology pharmacist and Think that will improve the patient treatment, and also makes possible to use the chemotherapy To groups that’s used not To Be possible the use. I’ll keep my eye In this technology!