Class IA PI3K Inhibitor Cancer Therapies

Class IA PI3K Inhibitor Cancer Therapies

Date: August 16, 2016

Author: Andrea Tarbet, Product Marketing Associate at ALPCO

Bruton’s tyrosine kinase (BTK) inhibitors are not the only kinase inhibitors to enter the fight against B cell cancers. Since there are numerous subtypes of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), patients around the world are in need of diverse treatments and cures. As a result, different types of kinase inhibitors that block the BCR signaling pathway are the focus of many drug research and development programs. More recently, investigators have been working to understand and identify Class IA PI3K inhibitor cancer therapies to improve patient outcomes.

Approved BTK and Class IA PI3K Inhibitor Cancer Therapies

In 2014, just one year after the FDA approved Pharmacylics’s BTK inhibitor Imbruvica (Ibrutinib) for mantel cell lymphoma (MCL), the agency approved the first phosphoinositide 3-kinase (PI3K) inhibitor, Gilead’s Zydelig (Idelalisib). Zydelig was approved to treat three types of relapsed B cell cancers including: chronic lymphocytic leukemia (CCL), follicular B cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL)1.

PI3K Classes and Isoforms

PI3Ks are involved in various cellular processes and widely expressed in humans2. Research over the past several decades has demonstrated that changes in the PI3K genes have been linked to different forms of human cancers3. These changes include mutations, upregulation, and even downregulation of the PI3K genes3.

There are several classes of PI3Ks with varying subunit isoforms, domains, and functions:

A chart outlining various PI3K Classes and Isoforms

The BCR Signaling Pathway

Like BTK, Class IA PI3Ks are part of the B cell receptor (BCR) signaling pathway. There are at least two different modes of activating the BCR pathway: chronic and tonic. Chronic activation requires an antigen to bind to the BCR, setting off the signaling cascade4. On the contrary, tonic activation does not require an antigen to activate the BCR pathway5. During both chronic and tonic BCR signaling, Class IA PI3Ks are activated to aid B cells. B cell cancers can rely on either chronic or tonic BCR signaling to grow4.

A chart demonstrating both chronic and tonic BCR signaling where Class IA PI3Ks are activated to aid B cells.

Isoform Specificity and Class IA PI3K Inhibitor Cancer Therapies

Originally, researchers tried targeting all forms of Class IA PI3Ks with drugs in development. However, the success of Zydelig with some B cell cancers has demonstrated how targeting specific isoforms can be more effective3. The next generation of Class IA PI3K inhibitors, such as TG Therapeutics’ PI3K delta inhibitor TGR-1202, have data illustrating how increased selectivity for the specific isoform can lead to an improved safety profile and efficacy against B cell cancers6,7,8.

Research on TGR-1202 also shows that the PI3K delta inhibitor is less toxic towards T cells than other Class IA PI3K inhibitors. This may account for the drug’s improved safety profile8. TGR-1202’s clinical trial to investigate and fully understand the drug’s safety and efficacy in patients with NHL, CLL, PTCL, and HL is slated to be complete by Fall 20169.

BTK and PI3K Inhibitors: Better Together?

Some research suggests that attacking B cell cancers from multiple fronts may improve patient outcomes. Research has demonstrated that when B cell cancer cell lines are treated with both the BTK inhibitor, Ibrutinib, and the Class IA PI3K inhibitor, Idelalisib, the drugs work together to target cancers relying on BCR signaling10. Since BTK and PI3K are both needed to activate NF-κB transcription factors vital for proper B cell function and survival, it is possible inhibiting both kinases will be more effective in treating B cell cancers10,11.

Additionally, preliminary data on the combination therapy of TGR-1202, Ibrutinib, and Ublituximab (a monoclonal antibody that helps eliminate cancerous B cells) has shown promising safety and efficacy in fighting relapsed and resistant B cell cancers such as NHL and CCL12. The results from this clinical trial are scheduled to be completed by early 201713.

Research is showing how PI3K isoform specific Class IA inhibitors, whether used alone or together, are effective in blocking the BCR signaling pathway in some relapsed and resistant B cell cancers. The next generation of isoform specific Class IA PI3K inhibitors demonstrates promising results. Further investigation into finding additional Class IA PI3K inhibitor cancer therapies can help improve the odds for patients around the world.

References

  1. Yao. (2014). FDA approves Zydelig for three types of blood cancers. Food and Drug Administration Press Release. FDA.gov.
  2. Jean et al. (2014). Classes of phosphoinositide 3-kinases at a glance. J. Cell Sci., 127(5), 923–928. PMCID: PMC3937771.
  3. Thrope et al. (2015). PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer, 15(1), 7-24. PMID: 25533673.
  4. Ortiz-Maldonado et al. (2015). The biology behind PI3K inhibition in chronic lymphocytic leukaemia. Ther. Adv. Hematol., 6(1), 25-36. PMID: 25642313.
  5. Srinivasan et al. (2009). PI3 Kinase signals BCR dependent mature B cell survival. Cell, 139(3), 573–586. PMID: 19879843.
  6. Friedman et al. (2012). Comparison of the PI3K-delta Inhibitors TGR1202 and GS-1101 in Inducing Cytotoxicity and Inhibiting Phosphorylation of Akt in CLL Cells in Vitro. 54th ASH Annual Meeting and Exposition. Poster #3914.
  7. O’Connor et al. (2015). Clinical Activity and Safety Profile of TGR-1202, a Novel Once Daily PI3K- Delta Inhibitor, in Patients with CLL and B-Cell Lymphoma. 2015 American Society of Hematology Annual Meeting. Abstract #4154.
  8. Maharaja et al. (2016). Differential Regulation of Human T cells by TGR-1202, A Novel PI3K-delta Inhibitor. American Association for Cancer Research Annual Meeting. Poster # 545.
  9. TG Therapeutics, Inc. (2013). Evaluate the Safety and Efficacy of TGR 1202 in Patients With Relapsed or Refractory Hematologic Malignancies. Clinical Trial NCT01767766.
  10. de Rooij et al. (2015). Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: A rationale for combination therapy. Blood, 125, 2306-2309.  doi:10.1182/blood-2014-12-619163.
  11. Matsuda et al. (2009). Critical role of class IA PI3K for c-Rel expression in B lymphocytes. Blood,113, 1037-1044; doi:10.1182/blood-2008-06-163725.
  12. Fowler et al. (2015). Safety and Activity of the Chemotherapy-free Triplet of Ublituximab, TGR-1202 and ibrutinib in Relapsed B-cell Malignancies. 2015 American Society of Clinical Oncology Annual Meeting. Presentation.
  13. TG Therapeutics, Inc. (2013). Ublituximab in Combination with TGR-1202 +/- Ibrutinib in Patients with B-cell Malignancies. Clinical Trial NCT02006485.