18 karma · joined March 11, 2015
There are several novel ways to deliver drugs to tumors in the brain in trials. Some use specially designed pumps, nanotechnology, and intra-arterial delivery (where a catheter is snaked to the tumor through blood vessels).
The problem is that all of these methods are experimental so they can't be used in combination. We're very hopeful that they are successful though!
We started with the basis that all brain cancer patients receive a standard of care that will do little to extend their lives. Only about 10% enroll in clinical trials in the US, which only test one drug at a time. Most of the clinical trials are performed on patients who have a regrowth of their tumor, which has little chance of responding to treatment.
309 Currently Open Trials for Glioblastoma, but only 75 for newly diagnosed patients. https://clinicaltrials.gov/ct2/results?term=glioblastoma&rec...
With 90% of the patients not enrolled in a clinical trial we wanted to design a commercial solution that could help patients today rather then relying on the standard of care.
We have collaborations with academic labs that are studying the heterogeniety of neurospheres cultured from multiple sites from the same patient's tumor. Ideally to get a more representative sample you would be able to obtain multiple samples from the same patient and derive a separate culture from each one.
We will not be seeking FDA approval for our service as it is not a drug or diagnostic for a disease. The pathway for us is as a CLIA certified service similar to other personalized genomics companies in cancer like Foundation Medicine.
We won't be replacing the pathologist report for the oncologist. We also don't obtain the tumor after their analysis and report. Our testing will be running in parallel.
We produce our report using test results from the actual patient's living tumor that we obtain from the operating room. Pathologists embed the tumor cells in paraffin wax, which kills the tissue.
2. Yes there are challenges with applying the drugs because the cells are in an artificial environment outside of the body. We have improved the standard conditions the cells are tested in and will continue to develop methods to make the petri dish more like the patient's brain.
3. Initially brain cancer chose us, my dad passed away from the disease two weeks ago.
1. There are indeed similar efforts in academic labs around the world. The constraint they face is lack of funding to expand their experiments beyond testing drugs on their small sized tumor banks.
Industry labs don't generally have access to primary (from patients) tumors so they have to partner with academics or contract research organizations (CROs). No one institution or CRO has a Glioblastoma tumor bank beyond around 100 patient samples.
These smaller tumor banks don't capture the heterogeniety of the patient population as a whole, so one of the advantages of being a company not tied to an institution is the ability to develop a substantially larger tumor bank that accomplishes this. We accomplish this by acquiring primary tissue through our testing service around the world.
Academics also often rely on standardized assay conditions and commercially available cell lines because their major incentive is to publish their results. Standard methods and cell lines are often preferred by reviewers and working with primary lines is difficult and expensive. Translation to response in patients isn't the primary objective of the screens.
2. Yes, Elizabeth Iorns, a former cancer biologist and the CEO of Science Exchange, is one of the part time YC partners.
Glioblastoma was actually the first tumor profiled for the Cancer Genome Atlas Project. http://cancergenome.nih.gov/cancersselected/glioblastomamult...
There have been four subtypes found in the disease, but all four are still treated ineffectively with the same standard of care chemotherapy (Temozolomide). To date none of these predictive biomarkers have led to a successful targeted therapy.
This was a personal frustration for me, as I had my dad's tumor sequenced for genetic mutations, but there were no targeted therapies that reach the brain in high enough concentrations to be effective.
This is an important distinction in personalized medicine specific to brain cancer, as many drugs do not cross the blood brain barrier. For example the most prevalent mutation in Glioblastoma is a mutation in the Epidermal Growth Factor Receptor (EGFR) pathway. This is also a driver mutation in lung cancer that has approved targeted therapies like Afatinib.
Unfortunately none of these drugs have worked in trials for brain cancer, in large part because they do not cross the blood brain barrier well. For example here is a study recently published on the poor results with Afatinib in brain tumor patients. http://www.ncbi.nlm.nih.gov/pubmed/25140039
There are currently very few targeted therapies in development for brain cancer as it is a small disease for pharma companies to market drugs.
This is why our approach is to correlate tumor response to existing therapies with empirically identified biomarkers. In contrast using tumors alone to predict cancer biomarkers is challenging because it requires a hypothesis or target to be tested one at a time with a novel therapy in a trial.
For underserved diseases like glioblastoma, this could result in many years passing by as each hypothesis driven therapy fails in clinical trials.
Yes we'll be testing combinations, as this brain cancer has not responded historically to single agent therapy for decades.
With combinations of existing drugs it is possible to affect multiple driver pathways in the tumor at once. Similar to the dramatic improvement of AIDS therapy and infectious disease treatment with cocktails, tumors could respond much differently to combinations instead of a "one at a time approach" that has resulted in very small survival gains in this disease.
Please see this paper for more detail on the scientific approach to mutli-agent combinations to target many pathways at once. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226667/
Patients have been taking the CUSP-9 protocol without any serious adverse affects on a compassionate use basis. This has now moved into a prospective clinical trial for recurrent glioblastoma patients in Germany http://www.anticancerfund.org/projects/cusp9-a-combination-o...
Personalized medicine services like this could allow clinicians to move beyond traditional randomized controlled trials. Commercial services such as Foundation Medicine provide test results to oncologists who then use their discretion to treat the patient outside of a clinical trial with scientific rationale based on the test itself as opposed to a standard of care.
In a severe disease like Glioblastoma where average survival is 15 months, if the majority of patients using a system like Notable Labs live substantially longer, is a control arm necessary? The HAART cocktail for AIDS treatment never went through a phase 3 trial, so there is precedent in high need diseases.
I also would like provide a link to a recent documentary that highlights the combination approach in brain cancer by telling the story of a 20 year survivor of Glioblastoma, Ben Williams. Other patients who safely used combinations of existing drugs are featured as well. http://www.survivingterminalcancer.com/
1. Great question, this is why we'll be focused on newly diagnosed glioblastoma patients. If they do recur and have a surgery to remove the recurrent (and hypothetically mutated) tumor, we would test that tissue as well and compare its drug response profile as well as any biomarker changes.
We'll also be using in vivo xenografts to try to model mutations/regrowths, by continuously observing treated mice to see if we get a regrowth. The mice have faster metabolisms than humans so tumors can sometimes regrow faster in them than in patients.
If we have a regrowth in a mouse, we could then culture that tumor in vitro for a screen to develop a plan to treat a patient's recurrence before it occurs. This has been proven out already as a strategy by another company using xenografts, Champions Oncology.
2. Since this LDT regulation change is still in motion we are observing it very closely. In discussions we've had with experts on the topic they have highlighted that any changes will be implemented gradually over time.
-Since all of the drugs are FDA approved we don't have to apply to get compassionate use as you would if you were obtaining an experimental therapy outside of a clinical trial. The approved drugs can be used at a doctor's discretion as an off label prescription within our current system. As for safety please see my response to the first comment.
-Yes we are going to be sequencing all of our tumors. The difference between our approach to this versus existing personalized medicine sequencing is that we're more interested in using biomarkers in the future once we've identified a patient population that responds to a certain drug combination.
This is our long-term goal, to use a patient's biomarkers to predict drug response that we can then validate in vitro and in vivo rather than just relying on empirically physically testing drugs on a patient's cells.
1. We agree, the reason we are using cell culture is because it is very fast and allows us to test many combinations at once. We have improved standard cell culture conditions and continue to do so to mimic the patient's brain as much as possible.
We confirm our results using in vivo mouse models where we have injected a patient's brain tumor cells into the mouse's brain.
2. Another great question, we prioritize the results based on safety first, then efficacy. Since these are exclusively approved therapies there is existing software that can predict toxicity interactions. We will also have a group of pharmacists that will validate the safety of the combinations.
3. This was one of the first hurdles we encountered after we started the company. The drugs we are testing are mostly off-patent generic drugs that are cheap for patients to buy directly without reimbursement from their insurance company.
If it is a more expensive drug, we can help the patient and their doctor appeal to get reimbursement on the rationale that the standard of care for grade 4 brain cancer is ineffective.
We will be starting a feasibility clinical trial as soon as we can for the purpose of publishing data on the safety and feasibility of this approach.
Step 1: The patient undergoes surgery to remove their brain tumor, which is sent to our lab where the cells are grown. Step 2: We use lab robotics to apply thousands of combinations of FDA-approved drugs directly to the cancer cells. Step 3: Notable Labs analyzes the test results and provides them to the patient’s doctor, who can prescribe the drugs immediately without a clinical trial. Step 4: Each treatment result allows us to algorithmically improve the drug selection process for future patients.
Glad to answer any questions!