Director of Translational Sciences https://www.linkedin.com/jobs/view/2227380667/?refId=WOv9NhH...Director of Medicinal Chemistry https://www.linkedin.com/jobs/view/2234535257/
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.
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.
Our approach increases the extracellular concentration of Dox and then it does the same job that it usually does.
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.
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.
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.
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:
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.
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.
More info can be found here:
https://blog.ycombinator.com/shasqi-first-in-human-clinical-...