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Preparation For Linnea's Virtual Review Board Meeting [Linnea Olson Hackathon]

Thanks for your continued interest and support for Linnea Olson. This is crunch time, culminating 3 months of conversation and research.

 

This weekly update (#14) finds Linnea in the hospital suffering from pneumonia and fluid buildup in her lungs, with fever, coughing, and vomiting.

 

She was unable to join the weekly call today.

 

She sent me this text: “I’m still getting IV antibiotics, but my last two readings have been 99.6 rather than over 100. Am going to have to be drained one more time and hopefully will be released tomorrow,” along with this scan:





Needless to say, we are all pulling for Linnea to emerge from this setback.

 

Despite being bedridden in the hospital, Linnea was able to request from her physician and share with us her Caris report. (If interested, you can see it on our online discussion forum – Slack.) There was one new mutation of note: KEAP1, which offers some new treatment options.

 

This turn of events has accelerated the need for advice on Linnea’s best next treatment option, assuming that her condition indicates the SHP2 trial she is on is not working.

 

Kimary Kulig, who has been an angel guiding our work for Linnea, summarized the situation:


  • Linnea’s physical condition means that the options she can realistically consider are limited to those with compassionate use or off-label uses, as she won’t meet the qualification criteria for clinical trials, e.g., cell-based therapies like TIL and CAR.

  • The Caris report (including the KEAP1 marker, low tumor mutational burden, microsatellite stable, and negative tests for PDL1 and other antibodies tested by IHC) indicate that some treatment options, e.g., immunotherapies and chemotherapy, are less likely to be responsive.

  • Linnea’s strategy should continue to be to bridge to the 4th generation ALK clinical trial from Turning Point, which will be available in the fall at MGH. (Expert Ross Camidge of the University of Colorado recommended this option in the last week, and it was also recommended by Linnea’s oncologists, Jess Lin and Alice Shaw, and Emily Venanzi.)

  • The most fruitful path looks like attacking KEAP1, for which there is a clinical trial by Calithera, which could be accessed through their expanded access protocol. Kimary’s bold opinion is that KEAP1 may be more important to address than the ALK pathway.


We have scheduled a virtual review board meeting for Sunday at 7:00pm Eastern to prepare our advice to pass on to Linnea and Linnea’s medical team on her best treatment path.

 

Our Requests

  1. Please review our shared working document on Linnea’s treatment options, and leave questions and comments there.

  2. Please join the conversation on our online forum (Slack) to review and comment on Linnea’s treatment options.


You can find my notes from the roundtable discussion and the session recording (35 minutes) below.

 

Thanks,

Brad




 

Here are my notes from the roundtable discussion with more details:


  • Will LaValley: Do we have downstream Nrf2 activation from the KEAP1? [Toxicology Reports: The Nuclear factor erythroid2-related factor2 (Nrf2), a master regulator of redox homoeostasis, is a key transcription factor regulating a wide array of genes for antioxidant and detoxification enzymes. It protects organs from various kinds of toxic insults. On the other hand, activation of Nrf2 is also correlated with cancer progression and chemoresistance. Downregulation of Nrf2 activity has attracted an increasing amount of attention as it may provide an alternative cancer therapy.]

  • Kimary Kulig: We don’t. The Caris report indicated that she’s got wild type for STK11. [Wikipedia: Serine/threonine kinase 11 (STK11), also known as liver kinase B1 (LKB1), which encodes a member of the serine/threonine kinase family, regulates cell polarity and functions as a tumor suppressor.] However, it doesn’t mean the LKB1 protein is being expressed. So we don’t know if STK11 is being hypermethylated. [Wikipedia: DNA methylation in cancer plays a variety of roles, helping to change the healthy regulation of gene expression to a disease pattern.

  • Brad Power: Over the last week you led work to take the load off Linnea in her quarterbacking role, since she has been incapacitated. With help from Grace Cordovano, you tried to get a HIPAA [Health Insurance Portability and Accountability Act] authorization.

  • Kimary: I felt this was an emergency, so I dropped everything and went online to find a HIPAA form that would allow Brad, on behalf of the hackathon, to get access to Linnea’s medical records, radiology images, NGS reports, Caris report, or anything like that. I sent it to Linnea and Dr. Lin with a note that she could use this form or something similar that they typically use. I got a thank you from Linnea, and no word from Dr. Lin. I also called Dr. Lin’s office and left messages, but haven’t heard back, and I don’t think anything was signed.

  • Brad: We have identified that we need to prepare for these eventualities in the future by having backups/partners/proxies for data, tissue, and care.

  • Will: I have seen in her document the suggestion for adding off-label treatment options, non-targeted therapies, metformin, and others. It’s important to consider them much earlier in the sequence of events, to run in parallel. They are low affinity binding in affecting the molecular activities, and they are multi-targeted, such as metformin. It may not be viable now. If she’s in the hospital it won’t happen there.

  • Jeff: Have you connected with her care partner?

  • Brad: I got her name. I asked Linnea if she would like to engage her. Linnea said she would. But Linnea hasn’t given me her contact information. I will ask again, though I don’t want to bother Linnea.

  • Jeff: It’s a way to offload some of Linnea’s work. They can provide some of the backup.

  • Ricardo Salgado: Supporting Dr. LaValley’s comments, I think that there are complementary therapies that would have been useful earlier.

  • Brad: This is consistent with Linnea’s expression of interest in any lines of therapy, beyond traditional western medical therapies.

  • Ally Perlina: If at some point if some kind of nutraceutical is in consideration, even though I wouldn’t hang my hat on it for the most effective treatment, I can suggest some things that would be beneficial biologically for addressing the KEAP1 and Nrf2 pathways, or at least wouldn’t be harmful, because we know of the reactive oxygen species and different oxidative damage that can be protected from simple nutraceuticals that exist right now, including some that act like metformin.

  • Brad: This reminds me of the Kasey Altman hackathon, where Kasey is taking an extra round of chemotherapy to bridge her to her next round of treatment — an immunotherapy clinical trial in the fall. We similarly need to get Linnea to the fall when the other clinical trials at MGH will be ready. And we also heard yesterday from Damon Reed of Moffitt Cancer Center, who advocates an evolutionary biology approach to cancer treatment of multiple strikes, rather than thinking of a knockout punch.

  • Ally: I am trying to put something together on label therapies in some synergistic combos, even two- or three-drug therapy options.

  • Brad: You have multiple opportunities: discuss it now, there’s Slack, our working document on treatments, and our review board meeting at 4:00 Pacific on Sunday.

  • Ally: I will have our CureMatch report ready by Sunday, and I can present it then. I am thinking we could address other mutations, e.g., P53, which could also be addressed by some of the TKIs [Tyrosine kinase inhibitor, a substance that blocks the action of enzymes called tyrosine kinases. Tyrosine kinases are a part of many cell functions, including cell signaling, growth, and division.

  • Brad: I sent 25 invitations to the experts identified mostly by Ricardo Salgado, Emily Venanzi, Linnea, and Kimary, and got a few responses, but none are available for our meeting on Sunday. So we will have time for you to share your options.

  • Kimary: Bevacizumab sounds great, but I’m not sure if Linnea would tolerate it right now. I’m a big fan of metformin and hydroxychloroquine, but I don’t think her doctors will go for that. 

  • Ally: I have a nutraceutical alternative that has similar targeting to metformin, but is weaker. The reason I mentioned bevacizumab is that it’s a monoclonal antibody, and if we have a rationale for a monoclonal antibody that could be more easily tolerated than a multi-kinase inhibitor and small molecules in general.

  • Kimary: She is being treated at a very conservative institution. Anything we present that is not listed in the NCCN guidelines or is published in a reputable journal won’t be accepted. 

  • Will: Many of the supplements require oral administration, which is a problem. And therapeutic dosing is hard with these treatments. It’s not an option where Linnea is now.

  • Kimary: There is also the issue of insurance reimbursement. If her physicians aren’t on board, then she won’t get reimbursement.

  • Will: That’s why this molecular integrative oncology therapy should have been considered much earlier as a parallel branch of her therapy with precision oncology targeting.

  • Ally: I was thinking about berberine with flavonoids, with good combinations and sources.

  • Will: I was asking about KEAP1 and Nrf2, because they could be upregulated with supplements, rather than being downregulated. It’s tricky.

  • Kimary: Regarding the list that we have, the only thing that I think is practical is the Calithera treatment via expanded access. It’s something we could get Linnea’s doctors to sign up for while Linnea is waiting for the Turning Point ALK drug in the fall. That’s a lifetime for Linnea. Having an open access program bodes well. And I would add metformin.

  • Jeff: The dietary restriction model of Filtricine has shown improvement. It’s another long-term candidate.

  • Kimary: As we do a retrospective on lessons learned, the management of Linnea’s tissue between the pathologists and Caris had a breakdown. Linnea should have had a tissue sherpa/bird dog/proxy/advocate. We are missing analyses I would have wanted to get. There were 4 blocks, or was it 4 slides exchanged? What was the cellularity of the tissue? There wasn’t enough sensitivity to not exhaust the tissue. They should return any unused tissue, but I imagine they throw it away or use it for their research.

  • Will: You should write a protocol that patients could use to manage their tissue.

  • Brad: As a patient who is learning all the time, I would struggle, even with a protocol, to manage my tissue. I don’t have a concept of a block vs. a slide. How big is a block? I imagine something that is an inch by an inch, but I know that it is from a needle biopsy, so it is much smaller. I may have seen a slide in biology in high school, but not since. The bigger issue is that without patient involvement or a sherpa/bird dog, the patient’s interests get short attention in the dynamics.

  • Will: We talk about patient centricity, but I heard a saying that sums it up well, “Patient preference matters.”

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