This article is more than 5 years old. Information may no longer be current.
Combination of signal target molecule inhibitors shows promise for CLL treatment
Click Here to Manage Email Alerts
NEW YORK — The combination of an Axl receptor tyrosine kinase inhibitor with a reversible Bruton’s tyrosine kinase inhibitor appears to have synergistic activity on chronic lymphocytic leukemia B-cell apoptosis, according to a presenter at Lymphoma & Myeloma 2015.
“Single targets have always been attractive as targets of signal transduction inhibition, and that’s because these pathways are often related to the pathogenesis of lymphoid malignancies,” Neil E. Kay, MD, professor of medicine at Mayo Clinic in Rochester, Minnesota, said during his presentation. “In particular we’re aware of the Bruton’s tyrosine kinase [BTK] and PI3 kinase delta, and their prototypic drugs ibrutinib [Imbruvica; Pharmacyclics, Janssen] and idelalisib [Zydelig, Gilead].”
Kay and colleagues have identified a third receptor tyrosine kinase (RTK) — Axl — that is present on CLL B cells and is targetable.
“The current B-cell receptor [BCR] signaling pathway inhibitors obviously are promising, but they are not curative alone and resistance develops,” Kay said. “There are issues for patients who discontinue ibrutinib, there are low-grade but chronic toxicities and of course there have been reports of the emergence of Richter’s syndrome.”
Thus, Kay and colleagues explored whether CLL B cells express other constitutively active RTKs and whether they share the same common signal mediators as other BCRs, leading to the discovery of the constitutively active Axl RTK.
Activation of Axl — a member of the TAM family — initiates various signaling pathways depending on cell types, such as cell survival, proliferation, apoptosis inhibition, migration, cell adhesion and cytokine production, Kay said. Further, previous data have shown that the overexpression of Axl in solid tumors and acute myeloid leukemia is associated with poor survival.
When Kay and colleagues evaluated whether Axl is associated with cellular kinases and lipases, their data showed Axl may provide a docking site for key signaling molecules, such as PI3K, Syk, Lyn and Zap-70.
Based on data from four patients, researchers then showed the drug TP-0903 (Tolero) downregulates the phosphorylation of Axl, the inhibition of which appears to induce robust apoptosis in CLL B cells even in high-risk 17p/11q CLL. TP-0903 exposure also leads to a reduction in XIAP and Mcl-1 — two anti-apoptotic proteins that are key to leukemic B-cell survivorship — as well as upregulation of BIM, Kay said.
To determine if the Axl RTK inhibitor can synergize with other signal inhibitors, Kay and colleagues then combined TP-0903 with ibrutinib — an irreversible BTK inhibitor — and TP-4216 (Tolero), a reversible BTK inhibitor. Combination index analyses showed six out of 10 patients with CLL demonstrated complimentary activity with the combination of TP-0903 and a reversible BTK inhibitor.
“These inhibitors are orally bioavailable and would be candidates for clinical trial testing,” Kay said. – by Alexandra Todak
For more information:
Kay N. Targeted inhibition of signal molecules as novel therapy for CLL. Presented at: Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies; Oct. 22-24, 2015; New York, New York.
Disclosure: Kay reports research/grant support from Celgene, Genentech, Gilead, Hospira, Pharmacyclics and Tolero, as well as other support from Celgene.
Perspective
Back to Top
Wyndham Wilson, MD, PhD
Neil E. Kay, MD, presented a talk titled “Targeted Inhibition of Signal Molecules as Novel Therapy for CLL” at the Lymphoma & Myeloma 2015 meeting. The focus of his presentation was on modulation of B-cell receptor (BCR) signaling through inhibition of Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K).Although activation of BCR has been hypothesized to play a central role in a number of lymphoid malignancies — including CLL and the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) — the most direct evidence comes from the robust clinical activity of ibrutinib (Imbruvica; Pharmacyclics, Janssen), which inhibits BTK, and idelalisib (Zydelig, Gilead), which inhibits PI3Kinase delta.
The broad clinical activity of BCR inhibitors across B-cell lymphoma types, including follicular lymphoma, mantle cell lymphoma, marginal-zone lymphoma, DLBCL and CLL/SLL speaks to the central role of BCR and antigen-driven survival in the pathogenesis of many, if not most, B-cell lymphomas.
BCR signal transduction lies at the heart of B-cell function, where it is a complex process involving interconnected pathways of effector molecules responsible for signal initiation, propagation, integration and modulation that modulates specific gene expression. BCR signaling thereby represents an important connection between intracellular signaling pathways and regulation of gene expression in the nucleus via NF-ĸB. Normal B cells requires a continuous (tonic) survival signal through BCR independent of antigen and mediated by PI3K. Antigen-induced BCR signaling (“chronic active”), in contrast, initiates a signaling transduction cascade of several tyrosine kinases and adapter molecules such as spleen tyrosine kinase (SYK), Lyn, PI3K, protein kinase C (PKCβ), and mammalian target of rapamycin (mTOR) to promote downstream survival pathways activated by NF-ĸB.
Oncogenic mutations within the BCR pathway have been best described in ABC DLBCL. Specifically, short hairpin RNAs screens have demonstrated toxicity for wild-type CARD11 but with no effect on ABC DLBCL cell lines with CARD11 mutations, suggesting that ibrutinib selectively kills DLBCL that relies on constitutive BCR signaling.
Mutations have also been described in the BCR receptor itself, involving CD79A and CD79B in ABC DLBCL. Clinically, ibrutinib has shown a 37% overall response rate in relapsed/refractory ABC DLBCL, but only 5% of germinal center B-cell (GCB) DLBCL, which have a low frequency of BCR activation.
The PI3K/Akt/mTOR signaling pathway also plays a central role in BCR signaling. PI3K signaling is activated by various mechanisms across B-cell malignancies and somatic mutations of PI3K genes likely contribute to the unregulated cell proliferation and metabolism in DLBCL. There are three classes of PI3Ks, with Class IA the most implicated in cancer. Class IA PI3Ks are activated by growth factors through numerous receptor tyrosine kinases and catalytic subunit isoforms that are potentially amenable to inhibition by small molecules. Idelalisib is a potent small molecule inhibitor of the PI3K isoform p110delta blocking constitutive PI3K signaling in vitro. In a phase 1 study, idelalisib was studied in nine patients with DLBCL and was well tolerated, but did not result in clinical responses. Of interest, drug resistance mechanisms to idelalisib in patients with mantle cell lymphoma were recently reported to occur via up regulation of the non-targeted isoform, PI3Kalpha11. This finding has critical implications regarding potential mechanisms of drug resistance to these inhibitors of BCR signaling.
References:
Brown JR, et al. Blood. 2014;doi:10.1182/blood-2013-11-535047.Courtney KD, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2009.25.3641.
Dal Porto JM, et al. Mol Immunol. 2004;41:599-613.
Davis RE, et al. Nature. 2010;doi:10.1038/nature08638.
Gauld SB, et al. Science. 2002;296:1641-1642.
Herman SE, et al. Abstract 185. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.
Iyengar S, et al. Blood. 2013;doi:10.1182/blood-2012-10-460832.
Lannutti BJ, et al. Blood. 2011;doi:10.1182/blood-2010-03-275305.
Srinivasan L, et al. Cell. 2009;doi:10.1016/j.cell.2009.08.041.
Wilson WH, et al. Nat Med. 2015;doi:10.1038/nm.3884.
Click Here to Manage Email Alerts