Page 16 - Haematologica - Vol. 105 n. 6 - June 2020

Editorials
of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007;109(11):4952-4963.
6. Piccaluga PP, Agostinelli C, Califano A, et al. Gene expression analy- sis of peripheral T cell lymphoma, unspecified, reveals distinct pro- files and new potential therapeutic targets. J Clin Invest. 2007;117(3):823-834.
7. Cortes JR, Ambesi-Impiombato A, Couronne L, et al. RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis. Cancer Cell. 2018;33(2):259-273.e7.
8. Heavican TB, Bouska A, Yu J, et al. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood. 2019;133(15):1664-1676.
9. Pedersen MB, Hamilton-Dutoit SJ, Bendix K, et al. DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study. Blood. 2017;130(4):554-557.
10. Drieux F, Ruminy P, Abdel-Sater A, et al. Defining signatures of peripheral T-celllymphoma with a targeted 20-marker gene expres- sion profiling assay.. Haematologica. 2020;105(6):1582-1592.
PIKing the next therapeutic target in multiple myeloma
Jessica L. Caro and Faith E. Davies
Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA E-mail: FAITH E DAVIES - faith.davies@nyulangone.org
doi:10.3324/haematol.2020.248971
Arguably the most transformative myeloma thera- pies to date have been those which target essential processes involved in plasma cell function. Although their mechanism of action may not have been entirely obvious when first introduced, it has now become clear from cell-based studies that these therapies target protein degradation via the ubiquitin proteasome pathway, a critical process for plasma cell survival. Examples include proteasome inhibitors (such as borte- zomib, carfilzomib, and ixazomib) and the immunomod- ulatory drugs (such as lenalidomide and pomalidomide), which inhibit the CUL4 E3 ubiquitin ligase, cereblon. Both drug classes are the ‘go to’ choices in current myelo- ma treatment.1 It therefore comes as no surprise that the search for other therapies targeting protein degradation pathways continues.
The key function of a normal plasma cell is to produce immunoglobulins. Studies have shown that myeloma plasma cells, which produce large quantities of M protein, are highly dependent on the multiple pathways that enable a cell to handle excess unfolded or misfolded pro- teins. Over the last 10 years, cancer researchers have explored many of these pathways with a view to thera- peutic exploitation. The rationale is that inhibition of these pathways leads to a build up of unwanted or mis- folded proteins, the induction of cellular stress, and ulti- mately to cancer cell death. Such pathways include not only the ubiquitin proteasome pathway but also the heat shock protein pathway, autophagy pathway, unfolded protein response pathway, and pathways involving lyso- somes and aggresomes.2 However, translating in vitro find- ings into clinical success has been difficult. It has become clear that some cancer types are dependent on one path- way more than others, the pathways are interlinked, and the crosstalk between pathways enables the development of both primary and drug-induced mechanisms of resist- ance.
In this edition of Haematologica, Bonolo de Campos et al. describe a promising new approach for myeloma therapy by perturbing the autophagy and lysosome pathways.3 In autophagy, misfolded and aggregated proteins are sequestered in double-membraned vesicles called autophagosomes that eventually fuse with lysosomes for digestion and recycling. Previous studies have shown that
myeloma cells require tight regulation of the autophagy pathway for cell survival, and genetic or therapeutic manipulation of this pathway induces growth inhibition and/or cell death.2,4,5
Phosphatidylinositol-3-phosphate 5 kinase (PIKfyve) is a phosphoinositide kinase with many diverse functions within the cell, including the generation of phosphorylat- ed substrates critical to the regulation of autophagy.6 Inhibition of PIKfyve using the selective inhibitor apil- imod has previously been investigated as a potential ther- apeutic approach for both inflammatory diseases and non- Hodgkin lymphoma.7 Using an unbiased chemical screen, Bonolo de Campos et al. identified APY0201 and exam- ined its activity along with that of apilimod and another novel PIKfyve inhibitor YM201636 in 25 human myeloma cell lines and 100 ex-vivo patient-derived samples. They confirmed dose-dependent inhibition of cell viability in all myeloma cell lines, with APY0201 being the most potent PIKfyve inhibitor. They additionally observed dose- dependent sensitivities in 40% of ex-vivo patient-derived samples with APY0201. Mechanistic experiments suggest- ed that exposure to APY0201 resulted in activation of the transcription factor EB (TFEB) leading to upregulation of autophagosome and lysosomal biogenesis. Exposure also disrupted lysosomal function leading to alterations in autophagic flux and a vacuolization phenotype.
As myeloma is a genetically and biologically heteroge- neous disease, it is critical to identify which patients would benefit most from a new therapy. The prime exam- ple of the need for such an approach is venetoclax, a Bcl-2 inhibitor, which has been shown to be particularly effica- cious in patients harboring a t(11;14) translocation.8 Although targeting a pathway central to plasma cell sur- vival should theoretically result in universal myeloma cell death, it has become clear that the genetic background of the cell influences response to therapy.9 For instance, whereas patients with a t(14;16) translocation tend to respond poorly to proteasome inhibitors, these therapies may be able to overcome some of the adverse outcome associated with the t(4;14) subgroup.10 Therefore, trying to incorporate genetic information into therapeutic decision- making may allow us to optimize treatment choices and response rates and to provide long-lasting remissions. Importantly, the authors have tried to assess this in their
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haematologica | 2020; 105(6)