&lt;p&gt;Lights and Shade of Next-Generation Pi3k Inhibitors in Chronic Lymphocytic Leukemia&lt;/p&gt;

Visentin, Andrea; Frezzato, Federica; Severin, Filippo; Imbergamo, Silvia; Pravato, Stefano; Gargarella, Leila Romano; Manni, Sabrina; Pizzo, Serena; Ruggieri, Edoardo; Facco, Monica; Brunati, Anna Maria; Semenzato, Gianpietro; Trentin, Livio

doi:10.2147/ott.s268899

Cited by 21 publications

(19 citation statements)

References 68 publications

(113 reference statements)

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“…The first example is the use of the inhibitor imatinib mesylate in chronic myeloid leukemia (CML), which targets the aberrant kinase activity of BCR-Abl1 [ 42 ]. Along this line, other kinases inhibitors, such as BTK (ibrutinib, acalabrutinib, and zanubrutinib) and PI3K (idelalisib, duvelisib, copanlisib, and others), have been developed among the therapeutic opportunities for blood malignancies [ 43 , 44 , 45 ]. Nevertheless, several mechanisms of resistance exploited by cancer cells have been reported [ 37 ].…”

Section: Protein Kinases Ck1α and Ck2 In Hematological Malignanciementioning

confidence: 99%

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Spinello

Fregnani

Tubi

et al. 2021

IJMS

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Disturbance of protein kinase activity may result in dramatic consequences that often lead to cancer development and progression. In tumors of blood origin, both tyrosine kinases and serine/threonine kinases are altered by different types of mutations, critically regulating cancer hallmarks. CK1α and CK2 are highly conserved, ubiquitously expressed and constitutively active pleiotropic kinases, which participate in multiple biological processes. The involvement of these kinases in solid and blood cancers is well documented. CK1α and CK2 are overactive in multiple myeloma, leukemias and lymphomas. Intriguingly, they are not required to the same degree for the viability of normal cells, corroborating the idea of “druggable” kinases. Different to other kinases, mutations on the gene encoding CK1α and CK2 are rare or not reported. Actually, these two kinases are outside the paradigm of oncogene addiction, since cancer cells’ dependency on these proteins resembles the phenomenon of “non-oncogene” addiction. In this review, we will summarize the general features of CK1α and CK2 and the most relevant oncogenic and stress-related signaling nodes, regulated by kinase phosphorylation, that may lead to tumor progression. Finally, we will report the current data, which support the positioning of these two kinases in the therapeutic scene of hematological cancers.

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Section: Protein Kinases Ck1α and Ck2 In Hematological Malignanciementioning

confidence: 99%

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Spinello

Fregnani

Tubi

et al. 2021

IJMS

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“…In particular, patients failing the Bruton's tyrosine kinase inhibitor ibrutinib and/or the B-cell lymphoma-2 (BCL2) inhibitor venetoclax are characterized by a poor prognosis and a short survival. [7][8][9][10] In this dismal clinical context, promising therapeutic successes have been achieved in relapsed/refractory B-cell malignancies with the infusion of CD19 chimeric antigen receptor (CAR)-T cells. 11 However, concerns have been raised on the accessibility of this therapy, as it is available only in a few centers for selected patients and at very high costs.…”

Section: Introductionmentioning

confidence: 99%

Innovative therapeutic strategy for B-cell malignancies that combines obinutuzumab and cytokine-induced killer cells

Pietà

Cappuzzello

Palmerini

et al. 2021

J Immunother Cancer

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BackgroundPatients affected by aggressive B-cell malignancies who are resistant to primary or salvage chemoimmunotherapy have an extremely poor prognosis and limited therapeutic options. Promising therapeutic success has been achieved with the infusion of CD19 chimeric antigen receptor-T cells, but several limits still restrain the administration to a limited proportion of patients. This unmet clinical need might be fulfilled by an adoptive immunotherapy approach that combines cytokine-induced killer (CIK) cells and monoclonal antibodies (mAb) to the CD20 antigen. Indeed, CIK cells are an effector population endowed with antitumor activity, which can be further improved and antigen-specifically redirected by clinical-grade mAb triggering antibody-dependent cell-mediated cytotoxicity.MethodsCIK cells were generated from peripheral blood of patients affected by different B-cell malignancies using a blinatumomab-based cell culture protocol. Effector cells were combined with the anti-CD20 mAb obinutuzumab and their therapeutic activity was assessed both in vitro and in vivo.ResultsCIK cells were successfully expanded in clinically relevant numbers, starting from small volumes of peripheral blood with extremely low CD3+ counts and high tumor burden. This relied on the addition of blinatumumab in culture, which leads to the simultaneous expansion of effector cells and the complete elimination of the neoplastic component. Moreover, CIK cells were highly cytotoxic in vitro against both B-cell tumor cell lines and autologous neoplastic targets, and had a significant therapeutic efficacy against a B-cell malignancy patient-derived xenograft on in vivo transfer.ConclusionsThe combination of an easily expandable CIK cell effector population with a mAb already in clinical use establishes a tumor antigen-specific redirection strategy that can be rapidly translated into clinical practice, providing an effective therapeutic alternative for B-cell malignancies without any need for genetic modifications. Additionally, the approach can be potentially applied to an extremely vast array of different tumors by simply substituting the targeting mAb.

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“…HSP70 and HSF1 inhibition, in fact, has been proven to be effective in inducing a dose-dependent in vitro apoptosis of CLL cells [9,10]. Moreover, supporting the implication of HSP70/HSF1 axis in Ibrutinib-resistance in CLL, PI3K/Akt pathway has been found to be hyper-activated in those patients [19,20].…”

Section: Introductionmentioning

confidence: 81%

Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia

Frezzato

Visentin

Severin

et al. 2021

Cancers

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The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations. The heat shock protein of 70 kDa (HSP70) and its transcription factor heat shock factor 1 (HSF1) play a role in mediating the survival and progression of CLL, as well as taking part in drug resistance in various cancers. We demonstrated that resveratrol and related phenols were able to induce apoptosis in vitro in leukemic cells from CLL untreated patients by acting on the HSP70/HSF1 axis. The same was achieved in cells recovered from 13 CLL patients failing in vivo ibrutinib treatment. HSP70 and HSF1 levels decreased following in vitro treatment, correlating to apoptosis induction. We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.

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<p>Lights and Shade of Next-Generation Pi3k Inhibitors in Chronic Lymphocytic Leukemia</p>

Cited by 21 publications

References 68 publications

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Innovative therapeutic strategy for B-cell malignancies that combines obinutuzumab and cytokine-induced killer cells

Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia

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