Precision Medicine Combination Treatment Shows Anti-Tumor Activity in Preclinical DLBCL Models

By Sucharita Mistry, PhD

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in adults. DLBCLs are aggressive and typically represent a heterogeneous collection of diseases that can be grouped into different subtypes depending on their particular genetic lesions.

One such subtype, described as the C3 or EZB cluster, features alterations in the BCL2 gene and mutations in chromatin remodeling genes such as EZH2. The malignant growth of this particular subtype of DLBCL is likely dependent on genetic abnormalities in EZH2 and BCL2. Both these oncogenes (genes with the potential to cause cancer) mediate their effects on tumor growth through distinct mechanisms, providing new opportunities for rational therapeutic strategies that inhibit EZH2 and BCL2 concurrently.

Dr. Lisa Roth and colleagues from the Weill Cornell Medicine and NewYork-Presbyterian Hospital Lymphoma Program evaluated the efficacy of EZH2 inhibitor tazemetostat and BCL2 inhibitor venetoclax as single agents and in combination using different preclinical models.

Tazemetostat and venetoclax were administered alone and in combination in a panel of DLBCL cell lines with and without mutations in EZH2 and translocation (a genetic abnormality in which a chromosome breaks and reattaches to a different chromosome) in BCL2. In DLBCL cells harboring EZH2 mutation and BCL2 translocation, the combination treatment markedly enhanced cell killing compared to either drug alone. Although these findings are encouraging, cell culture models are limited as lymphoma cells grown on a plastic surface in liquid cultures cannot recapitulate the physiologic environment within the human body.

To test the efficacy of the drugs in models with increased clinical relevance, Weill Cornell researchers established three-dimensional (3D) organoids that closely mimic the lymph node architecture in humans. The tazemetostat/venetoclax combination therapy was tested in two different novel organoid systems 1) organoids derived from lymphoma cells, and 2) patient-derived xenograft (PDX) organoids generated from a patient tumor and propagated in mice. The PDX tumor carried both EZH2 mutation and BCL2 translocation. In both types of organoids, tazemetostat and venetoclax had minimal activity as single agents, whereas the tazemetostat/venetoclax combination resulted in significant cell killing.

Using novel model systems, this study demonstrated that EZH2 inhibition combined with BCL2 inhibition results in synergistic anti-tumor effects. Learn more about the findings here.

Lisa“The synergistic anti-lymphoma activity mediated by the combination of tazemetostat and venetoclax is quite promising,” says Dr. Roth. “This combination therapy is anticipated to be especially effective as precision therapy for DLBCL patients with EZH2 mutation and BCL2 alteration.”

A clinical trial of this combination treatment is currently in development in collaboration with Drs. Ari Melnick, John Leonard and Peter Martin.

 

Weill Cornell Medicine Launches New Podcast Hosted by Dr. John Leonard

We are thrilled to announce the launch of our brand-new podcast, CancerCast: Conversations About New Developments in Cancer Care, Research, and Medicine.

Hosted by the Lymphoma Program’s own Dr. John Leonard, CancerCast provides a window into the latest research breakthroughs, innovative therapies, and honest accounts of living with and beyond cancer. This podcast is an excellent resource for patients, caregivers, and all others with an interest in science and medicine.

Here’s a preview of what CancerCast has in store:

  • An expert synopsis of the hottest topics in cancer research and treatment, including precision medicine, immunotherapy, and liquid biopsies to capture circulating tumor DNA
  • Anxiety management strategies for patients and caregivers
  • One patient’s experience coping with cancer as a young adult
  • An overview of the present and future states of CAR-T cell therapy
  • And much more!

We welcome our Lymphoma Program community to download, rate and review CancerCast, now available on Apple Podcasts, Google Play Music, and online at weillcornell.org.

Questions or suggestions can be directed to CancerCast@med.cornell.edu.

Happy listening!

 

My Name Is CC, and I Am a Cancer Survivor

“Hello, my name is CC, and I am a cancer survivor.”

I never thought that those words would sit together in the same sentence, let alone with a great deal of comfort and elbow room. I never thought that the word “cancer” would be applied to me at all. And I never thought that I would carry the words with me still, after it was all over. You see, I was hoping I would be able to tuck cancer away, someplace small and sacred, and be able to forget that I was ever that sick, forget that I ever did all that chemo, and forget that my life was forever changed.

But that’s not what happened. That’s not the story.

I was young. I was active. I was social. I was ambitious in my career and excited about the future. I was a “healthy” and “normal” 29-year-old when I was diagnosed with stage IV Hodgkin lymphoma in the sleeting February of 2016. After getting totally emotionally sidelined by the diagnosis, I completed six rounds (12 infusions total) of ABVD chemotherapy. That’s a total of 36 hours in the infusion center’s bustling waiting room, 72 hours in the chemo chair, watching 259,200 drips trickle down from the chemo bag into the big blue vein in my arm. That’s 12 lightly toasted bagels from the café downstairs, an infinite number of hand holds and arm rubs from my mother, and countless times the floor dropped out from beneath me to swirl with the walls.

WebsterSisters
With my sister, Ashley, in July 2016, before my final treatment.

When I tumbled out the other side into remission that sweaty August, I tried to pick up my life and career where I had left it, but it just wasn’t the same. Something was missing. It was like my doctor had sent me home with a stick shift when I only knew how to drive an automatic. Everything I had built for myself had seemed to disappear, sinking between my fingers. All of my dreams and my excitement for the future fell in a heap on the floor, having lost their glitter and gleam. I had to rebuild by finding and following my sense of joy, passion, peace and purpose.

My observations and perspectives surrounding my experience with cancer may ring true to anyone who has sat in that chemo chair, or who has shown up to a cocktail party with a fresh buzz cut. But more than a cancer story, my story is one of facing challenge and surviving. It is a story about the power of the physical body and the emotional self. It is a story about love. And most of all, it is story of hope, with a little bit of humor.

I want to tell my story in this blog post and in the next ones to come, with this community specifically, because this is where I came for help, too. Stay tuned. I can’t wait to share my story with you.


CCWebster_PhotoCC Webster is a recent survivor, patient of Weill Cornell Medicine/NewYork-Presbyterian (WCM/NYP), and author of So That Happened, a memoir that offers a candid reflection on her experience with cancer as a young adult. Diagnosed with Hodgkin lymphoma at the age of 29, CC completed treatment under Dr. John Leonard and his team at WCM/NYP’s Lymphoma Program. Now in remission, she is sharing her story, perspective, and insights in hopes of raising awareness of the disease and helping others through the battle – always with a little bit of humor. Her book is available on Amazon, Barnes & Noble, Goodreads, and through her site and publishing platform Webster Works. CC lives with her husband, Matt, in New York City.