Weeks 172 & 173: Testing times

Written by Lars Haakon Soraas
17
Dec

Weeks 172 and 173 in the war on lung cancer have passed. First a summary of what has happened in the past two weeks, then the current plan, and then the leads we are working on. As will become evident from the summary below, these are testing times. We thus solicit help from anyone who thinks they may be able to help us defeat this monster. The help we could need include assistance with analyzing both DNA and RNA sequencing data, testing of tumor tissue and getting hold of promising drugs. If you think you can help with any of this, then please do read the last section of this blog post (“The leads we are working on”) and contact me on larshaakon@gmail.com.

The past two weeks

  • While on holiday on Penang, Malaysia, Dyanne started feeling some numbness in her left chin and on the lower left side of her mouth and tongue. From being barely noticeable, the numbness has gradually gotten worse. An MRI scan of the brain, which was done in the past week, has found the probable cause of this numbness: a metastasis at the base of the skull. We hope that Radiumhospitalet, the hospital here in Oslo where Dyanne is treated, can radiate this before Christmas. If they cannot, we may well become medical tourists again and travel somewhere that can do this on short notice.
  • Dyanne did a CT scan this past week, but we do not yet have the results. Radiumhospitalet apparently have long delays in evaluating the CT scans they take. I guess it is best to shut my mouth and not write what I think about that.
  • As mentioned in the last post, we recently discovered what we thought was an enlarged lymph node above Dyanne’s collar bone. We figured that since this was a relatively large ensemble of enemy cancer cells, we should try to take them hostage so we could interrogate and analyze them. We thus decided to do surgery to remove the tumor. This was done on Thursday this past week. The surgery went smoothly and a lot of tumor cells were removed. Probably at least a hundred million or so. The less than good news is that the surgeon did not manage to remove the whole tumor. It was not only in the lymph node, but also in the soft tissue. The tumor went down towards the mediastinum and was also attached to blood vessels. He could thus only remove around three quarters of it. The surgery gave us a lot of tissue, but it also revealed that the tumor is very aggressive and fast growing.
  • The removed tumor tissue is currently being analysed and tested in various ways. We hope to get some results this coming week. A part of the tumor is also en route to StoreMyTumor. StoreMyTumor is basically a biobank that offers to cryo-preserve and store tumors from patients so that they can be used in the future for a range of purposes. As technology moves fast, there may be things one can do in the future with tumor tissue that is today not possible. Thus we figured it makes sense to keep some of the tumor in storage. We hope this biobanking pays off better than savings accounts do.
  • Cegat GmbH has finished sequencing Dyanne’s tumor and normal DNA, as well as tumor RNA. The data is around 50 GB and is currently being analysed by some bioinformaticians. The analysis can both help us understand more about the monster we are dealing with, and can potentially also open up for new treatment opportunities. The most interesting finding so far is that most of the mutations found in the cancer cells are consistent with what is called “mutational signature 3” (see here for details). This signature is, coincidentally, the signature that is found in tumors that are caused by either germline or somatic BRCA mutations. Dyanne does not have any BRCA1 or BRCA2 mutations and one question is then what is causing these mutations. A second question is if this can somehow be used to guide treatment. The high level of chromosomal instability that Cegat mentioned in their report is consistent with the finding of this mutational signature 3.

The plan

The plan is still work in progress, but here are the immediate action points:

  • There is urgency in getting the metastasis at the base of the skull radiated. We hope this will happen this week in Oslo. If not possible, we will probably travel somewhere else in Europe to get it done.
  • There is urgency in starting a new systemic therapy. This is currently scheduled for Wednesday this week. And the plan is to start with the chemo combination carboplatin and pemetrexed.
  • There is also urgency in getting the reports from the CT and MRI scans so that we get a clearer picture of the situation.

The leads we are working on

Although chemo and radiation are being planned, we have no illusion that this will give us very long respite. Maybe we are lucky and chemo works for a year year. More realistically it will keep cancer in check only a few months. And worst case scenario it won’t work at all. We are thus, with urgency, working to plans B and C and D. Here are some of the leads we are working on:

  1. The testing done by Cegat has revealed that Dyanne has a mutation in the PIK3CA gene. The mutation is one of the most common mutations found in this gene: E542K. A drug developed by Novartis has recently shown promising results in women with breast cancer who have mutations in the same gene. The drug is called alpelisib and is not yet approved. No one knows if it will work as well in lung cancer as in breast cancer, but it does seem like a promising drug to try – if we can manage to get hold of it. Here is more info on alpelisib: https://www.onclive.com/web-exclusives/lead-researcher-discusses-alpelisib-in-pik3ca-breast-cancer.
  2. The finding of a high level of chromosomal instability and many mutations that can be classified as belonging to “mutational signature 3” is an interesting lead. This suggests that Dyanne’s lung cancer is similar to BRCA mutant breast and ovarian cancer. Can some of the treatments developed for BRCA mutant breast and ovarian cancer patients work for Dyanne? No one knows, but it is certainly an interesting idea to explore.
  3. There has recently been published two very interesting pre-clinical papers on how resistance to the type of drug Dyanne currently is on (osimertinib) can be overcome.
    • The first paper suggests inhibition of Aurora kinase A (AURKA) is important. An investigational drug called alisertib blocks AURKA. Alisertib could thus be a very interesting drug to get hold of.
    • The second paper suggests that inhibition of PKCdelta can overcome resistance to drugs like osimertinib. An investigational drug called sotrastaurin can block PKCdelta and seems to work very well in the lab when combined with osimertinib. Sotrastaurin, or any other drug that blocks PKCdelta, would thus be interesting drugs to get hold of.
  4. The aggressive behaviour and rapid growth of the current tumor we are fighting suggests that the cancer cells have somehow been changed. One possibility is that they have transformed into some form of a neuroendocrine tumor. Testing is currently ongoing to see if this can be the case or not. If it is, then perhaps this can open some therapeutic opportunities.
  5. As mentioned, we have had DNA and RNA sequencing done on Dyanne’s recent biopsy. The data reveals a lot about the tumor, but it is a large amount of data (~50 GB) and it is complex. Can this kind of data be analyzed and help determine the best treatment? I believe it can. Humankind may not be there completely yet, but many are working on such approaches. If you are one of them and would like to help analyze and interpret our data, do please contact me.
  6. Finally, as mentioned above, we do have some tumor tissue that is now banked with StoreMyTumor. Analyzing this further, and potentially using it to develop treatments, is of great interest. Can you help with this, then please do reach out.

If you can help get access to any of the drugs mentioned above, or if you can help analyse any of our data or tumor tissue, then please do not hesitate to contact me on larshaakon@gmail.com.

These are, undoubtedly, testing times. It has been some rough weeks. At the same time, we have access to an unprecedented amount of tumor tissue, and a vast amount of sequencing data. With some intelligence, whether human or artificial, I imagine it should be possible to outsmart this monster. Any help in this endeavor is greatly appreciated.

Let me end with saying a huge thank you to all the people who have helped us in a myriad of different ways in the past few weeks. I won’t mention names; those who have helped us know who they are. The support and guidance we are getting from a number of researchers, doctors and others truly is invaluable for us. Thank you very much for everything you do for us.

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