New Research: How Inherited DNA -Based Mutations Impact Immunotherapy

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New Research: How Inherited DNA -Based Mutations Impact Immunotherapy

Scientist using multi-channel pipette for pipetting a 96 well plate with red solution on blue. Genetics experiment in biological laboratory

The partners on the UCLA research team have made new discoveries about how genetic mutations can help doctors predict patient responses to cancer-fighting immunotherapy drugs.

In the past, we’ve spoken a lot about the Central Dogma, which is the idea that genetic information flows from DNA to RNA to proteins. Specifically, a strand of DNA is copied into RNA, a process called transcription, and then the RNA, or messenger RNA (mRNA), provides a “code” which makes a protein, a process known as translation.  This process has long represented our understanding of DNA. Just recently, scientists discovered a new class of RNA that is copied from the DNA but never gets translated into a protein.  Research into these previously neglected sections of the DNA, the “non-coding regions,” have revealed a treasure trove of information, including the discovery of a new inherited class of DNA based mutations, like the KRAS-variant.

How non-coding parts of our DNA predict cancer risk and treatment response

The bulk of MiraKind’s research is centered around trying to understand how mutations or genetic differences in these non-coding parts of a person’s DNA can predict both their risk for cancer, as well as how they will respond to cancer treatment.  One significant discovery we have made, for example, is that women with the KRAS-variant are at an increased risk for developing breast and ovarian cancer.  Further, that risk that is elevated when these women are faced with a drop in estrogen (i.e. due to menopause, surgery to remove the ovaries before menopause, etc.).

The role of genetics in predicting response to immunotherapy

Our current research, in collaboration with our sister company, MiraDx, explores how people with mutations like the KRAS-variant will respond to cancer therapy. We are focusing on immunotherapy,  a cancer treatment designed to activate a patient’s immune system to help fight their cancer.

Among the best known immunotherapies are a class of drugs called  “checkpoint inhibitors.” T cells are the soldiers of the immune system, patrolling the body to look for abnormal cells that may harm the body.  In some cases, tumors have found a way to hide from these T-cell “checkpoints” by masking their abnormal proteins so that they appear to be regular healthy cells.  Checkpoint inhibitors are drugs designed to “expose” a person’s tumor to their immune system by disabling the tumor’s ability to disguise itself. When the tumor is exposed, the immune system is free to attack it. For some patients, this is a very effective treatment. But, for others, it can lead to some serious side effects when their immune system instead attacks healthy parts of their body, like the liver, lungs, pancreas, skin, or even their heart. However, physicians cannot currently predict which of their patients will have these types of side effects to immunotherapy. We have recently learned that genetic mutations in the non-coding regions of the DNA provide important clues!

Our study findings

In our study, we wanted to see how checkpoint inhibitors impact people with special genetic mutations like the KRAS-variant. We first looked at 60 melanoma patients in whom we found a group of non-coding DNA mutations that were able to predict with 90% accuracy when a patient would have a toxic reaction toxicity to treatment with a checkpoint inhibitor. We then tested if those same mutations would also predict toxicity for patients with other cancer types who received immunotherapy. And, in fact, they did! We are currently extending our testing to patients with cancer of all types, to prove that these non-coding mutations will predict toxicity to immune therapy for everyone, based on their genetics, not their tumors.  Our end goal is to help doctors personalize patient care so that they can protect patients from these sometimes life-threatening side effects.

The research team on the first report of this project consisted of MiraDx in collaboration with Dr. Joanne Weidhaas, Kirk Wilenius, Aaron Wolfe Scheffler, Juliana Higa, Donatello Telesca and Mark C. Scholz.  The team recently presented our findings at the GU American Society of Clinical Oncology meeting.

This study brings us that much closer to helping us create more personalized healthcare solutions based on the unique genetics of each patient.

Do you have a question about this research? Ask us in the comments below!

 

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Comments

  1. Thank you for all the work you do!!!
    I find your studies fascinating (as much as I understand!) and hopeful!
    My brother & I are both cancer survivors (no others in family as far as we know). He had melanoma in his 40’s then prostate cancer early 50’s. My breast cancer, stage III, hormone pos, in one breast and pre cancer in other breast. I am BRCA neg but wonder if you studies will eventually show an inherited gene, especially since my father is a Holocaust survivor (he was 9 yrs old when war broke out).
    What about studies about inheriting mutations due to previous generation & trauma?

    • This is a very interesting question, and I do not know the answer. There is some good evidence that stress can change DNA methylation, and those changes can be passed on to offspring. Thus, I think it is possible!

  2. Is there currently any immunotherapy available for KRAS variant metastatic colon CA? If so how would one go about getting the above testing to assure there would be no toxic effect. I keep hearing from different medical professional about Opdivo for mCRC even though it is not “officially” approved and it was my (very limited) understating that check point inhibitors w a KRAS variant did not work, and could even be detrimental, but now there appears to be many oncologists questioning that?

    THANK YOU for all you do! Because of all your relentless hard work and sharing of your research we challenge the standard treatment plan my brother receives on a regular basis and if nothing else let the oncologists know we are somewhat educated in the different treatment options to keep them on their toes and provide cutting edge care to him.

  3. I 49 yrs old I have stage 4 breast cancer mine is er+ I looking to see if i can get into the study

    • Dear Mrs. Johnson,
      Yes of course we would be happy to have you join our studies. Please take the eligibility survey at mirakind.org. We will consent you and get you a cheek swab.
      Best
      Joanne

  4. If we have anyway supplied a cheek swan, can we find out if immunotherapies would be a good or dangerous option for us specifically? If not, Will there be testing oncologists can perform to help determine response to immunotherapy and how far off do you think this testing may be?

    • Hi Mrs. Montgomery,
      You can! Although we will likely prefer a fresh swab for our ImuDx test at MiraDx.
      Best
      Joanne

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