MCL-247: Durable Response of a Patient with a Mantle Cell Lymphoma Central Nervous System (CNS) Relapse to Treatment with a Bruton Tyrosine Kinase Inhibitor (BTKi) Monotherapy

Rios, Adan; Rekoff, Gregg; Dinh, Brian; Chen, Lei; Wahed, Amer; Nguyen, Nghia D.

doi:10.1016/s2152-2650(20)30862-4

Cited by 1 publication

(5 citation statements)

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“…In relapsed and refractory MCL CNSi, monotherapy with BTKi has been proven to be effective, with an objective response rate of 68%. This efficacy is attributed to the ability of these drugs to cross the BBB and reach the tumor site . The permeability of JS25 on the BBB was evaluated using an in vitro HBEC-5i cell model.…”

Section: Resultsmentioning

confidence: 99%

“…This efficacy is attributed to the ability of these drugs to cross the BBB and reach the tumor site. 34 The permeability of JS25 on the BBB was evaluated using an in vitro HBEC-5i cell model. Ibrutinib and acalabrutinib were included as controls.…”

Section: Resultsmentioning

confidence: 99%

“…However, this does not devaluate the therapeutic potential of JS25 in brain cancers, since higher retention rates can result in longer pharmacological effects, depending on the intracellular metabolism involved. Besides, clinical treatment with acalabrutinib (which showed a similar retention rate to JS25) did not affect the quality of the response to MCL-cell infiltration in the brain …”

Section: Discussionmentioning

confidence: 95%

“…Besides, clinical treatment with acalabrutinib (which showed a similar retention rate to JS25) did not affect the quality of the response to MCL-cell infiltration in the brain. 34 As a proof of concept of the therapeutic potential, mice with BL were treated with JS25 and presented a reduction of 30− 40% in the size of their solid tumors, and an overall reduction in metastasis and secondary tumor formation, relative to ibrutinib. The percentage of metastatic cells present in the liver, lungs, brain/meninges, and spinal cord/bone marrow was similar between treated groups (30% reduction), although lower with a higher JS25 dosage (70% reduction).…”

Section: ■ Discussionmentioning

confidence: 99%

“…Besides, clinical treatment with acalabrutinib (which showed a similar retention rate to JS25) did not affect the quality of the response to MCL-cell infiltration in the brain. 34 …”

Section: Discussionmentioning

confidence: 99%

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Selective Inhibition of Bruton’s Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors

Sousa

Almeida

Barahona

et al. 2022

ACS Pharmacol. Transl. Sci.

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Bruton’s tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK’s inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt’s lymphoma, causing a 30–40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% “on-target” efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: ■ Discussionmentioning

confidence: 99%

“…Besides, clinical treatment with acalabrutinib (which showed a similar retention rate to JS25) did not affect the quality of the response to MCL-cell infiltration in the brain. 34 …”

Section: Discussionmentioning

confidence: 99%

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