The Role of PI3K Inhibitors in Relapsed/Refractory FL and MZL - Episode 1

Overview of PI3K Inhibition in Lymphoma

Ian W. Flinn, MD, PhD, leads the discussion on the various PI3K isoforms and their role in lymphoma.

Jason M. Melear, MD: Hello, and thank you for joining us for this Targeted Oncology™ presentation titled “The Role of PI3K Inhibitors in Follicular Lymphoma and Marginal Zone Lymphoma.” The PI3K/AKT/mTOR pathway plays a key role in regulating processes central to cancer progression. PI3K inhibitors have come to play an increasingly important role in the management of relapsed or refractory indolent lymphomas. Today we will discuss the role of PI3K inhibitors in the treatment of follicular lymphoma and marginal zone lymphoma. We will also review data from recent clinical trials. I am Dr Jason Melear, a hematologist and oncologist with Texas Oncology in Austin, Texas. Joining me is my colleague Dr Ian Flinn, who is the director of the lymphoma cancer research program at Sarah Cannon Research Institute in Nashville, Tennessee. Thank you for joining us. Let’s begin. Dr Flinn—Ian—maybe you could start by giving us an overview of what PI3K is and how it relates to these lymphomas.

Ian W. Flinn, MD, PhD: Absolutely, Jason. PI3K is a family of lipid kinases that play a pivotal role in signaling events that occur at the cell surface. They are important in neoplastic transformation in B-cell survival and the transformation of B cells as well as other malignancies. In lymphoma, as I said, they relate to this nexus of signaling events, including the B-cell receptor [BCR] pathway. They also transmit other signaling events from the cell surface that are important in proliferating the malignancy. As a consequence, they have become a target for some of the therapies that we are going to talk about today.

Jason M. Melear, MD: They are used to treat not only lymphomas but also other solid tumors. They seem to be able to treat cancer in general.Ian W. Flinn, MD, PhD: Exactly. We may think about them—at least I think about them in my practice—as being for lymphomas, but you’re right. They are being looked at across different malignancies. We’re going to talk about that in a minute, but there are different PI3-kinases that are important in different malignancies. There’s discussion about whether you want a selective inhibitor of isoforms that are prevalent only in patients with lymphoma vs ones that are more broadly applicable. Just to dial down on that on a little—if we think about the PI3-kinases, there are basically 4 isoforms: alpha, beta, delta, and gamma. The delta isoform was the form that was first of interest in hematologic malignancies and in B-cell lymphomas, specifically because its expression is limited to cells of hematopoietic origin. 

Therefore, you may write and say, “If I could inhibit just the delta isoform, then maybe we would not get the adverse events or toxicities associated with inhibiting some of the other isoforms.” That was 1 of the initial hypotheses behind the development of the first PI3-kinase inhibitor, which was idelalisib. The other isoforms are important. For instance, when treating breast cancer, these other isoforms may be important. They may be important in lymphomas as well. The delta isoform is specifically for cells of hematopoietic origin—we do know that—but by inhibiting some of the other isoforms, it might be important as well. For instance, the gamma isoform is inhibited by both the delta and gamma isoforms and inhibited by duvelisib. The gamma isoform might be important because it provides some of those cell-cell interactions in the microenvironment that maintains the malignant cell. By inhibiting that, maybe we will pick up some efficacy.


For some diseases, when treating them, we know there is upregulation when patients become refractory. There are some patients for whom those other isoforms become important. For instance, for patients with mantle cell lymphoma, after multiple prior therapies, we know that there is an upregulation of that alpha isoform. The drug, copanlisib, was not indicated in mantle cell lymphoma. It might be useful there because while it’s generally a pan-inhibitor, most specifically alpha and delta isoforms, there may be a use for that drug that might be investigated in the future. It is not simple. We cannot think of these as static systems; they can change. That’s basically the rationale for trying to inhibit the PI3K.

Jason M. Melear, MD: Thanks.

This transcript has been edited for clarity.