Safety and Efficacy of the BCL Inhibitors Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Hantel, Andrew; Wynne, Joseph; Lacayo, Norman J.; Khaw, Seong Lin; Rubnitz, Jeffrey E.; Mullighan, Charles G.; Schmidt, Michelle; Zhou, Ying; Ross, Jeremy A.; Rosenwinkel, Lindsey; Kim, Su Young; Jabbour, Elias; Alexander, Thomas

doi:10.1016/j.clml.2018.07.016

Cited by 9 publications

(7 citation statements)

References 2 publications

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“…As in the cell line empirical-sensitivity data case, patient blood cancers shared predicted-drug sensitivity profiles with SCN tumors. These shared profiles included the BCL2 inhibitor ABT-263, which is in a class of drugs approved to treat chronic lymphoblastic leukemia, and is in development for other hematological malignancies (Hantel et al, 2018;Seymour et al, 2018) (Figures 8E and 8F). Thus, we observe a similarity between SCNCs and blood cancers that spans gene and protein expression, and drug sensitivity and gene vulnerability profiles.…”

Section: Concordant Gene Expression-based Drug Sensitivity Profiles In Scn and Blood Tumorsmentioning

confidence: 99%

Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies

Balanis¹,

Sheu²,

Esedebe³

et al. 2019

Cancer Cell

114

121

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Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies. SignificanceSCNCs are aggressive and histologically similar across tissue types, and no effective treatment modalities are available. Lung and prostate adenocarcinomas can transdifferentiate to SCNCs in response to targeted therapy. This has important consequences in that SCNCs, once considered rare, may become increasingly common with the emergence of resistance cases from targeted therapies. Here we define molecular signatures for SCNCs, and we find that SCNCs share similar drug and RNAi vulnerabilities with blood cancers. Our results guide the detection of SCN-like cases in the clinic, and support the exploration of treatments for SCNCs that mimic treatments for blood cancers.

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Section: Concordant Gene Expression-based Drug Sensitivity Profiles In Scn and Blood Tumorsmentioning

confidence: 99%

Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies

Balanis¹,

Sheu²,

Esedebe³

et al. 2019

Cancer Cell

114

121

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“…Finally, the toxicity profile of navitoclax is a concern. In clinical studies of navitoclax, dose-limiting thrombocytopenia and neutropenia have been reported [ 178 ], which may limit its translational applicability at cytotoxic doses in cancer patients who may already have diminished marrow reserves after chemotherapy. This may necessitate the evaluation of lower doses of navitoclax for senolysis, or potentially in combination with other less toxic senolytics.…”

Section: Senescence Targeting In the Treatment Of Cancer And Other Diseasesmentioning

confidence: 99%

The redox-senescence axis and its therapeutic targeting

et al. 2021

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Significance Cellular growth arrest, associated with ‘senescence’, helps to safeguard against the accumulation of DNA damage which is often recognized as the underlying mechanism of a wide variety of age-related pathologies including cancer. Cellular senescence has also been described as a ‘double-edged sword’. In cancer, for example, the creation of an immune-suppressive milieu by senescent tumor cells through the senescence-associated secretory phenotype contributes toward carcinogenesis and cancer progression. Recent advances The potential for cellular senescence to confer multi-faceted effects on tissue fate has led to a rejuvenated interest in its landscape and targeting. Interestingly, redox pathways have been described as both triggers and propagators of cellular senescence, leading to intricate cross-links between both pathways. Critical issues In this review, we describe the mechanisms driving cellular senescence, the interface with cellular redox metabolism as well as the role that chemotherapy-induced senescence plays in secondary carcinogenesis. Notably, the role that anti-apoptotic proteins of the Bcl-2 family play in inducing drug resistance via mechanisms that involve senescence induction. Future directions Though the therapeutic targeting of senescent cells as cancer therapy remains in its infancy, we summarize the current development of senotherapeutics, including recognized senotherapies, as well as the repurposing of drugs as senomorphic/senolytic candidates.

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“…40,[52][53][54] Venetoclax, a BCL2 inhibitor, has shown promising results in early clinical trials for both refractory ALL and MCL. 42,55 Using human ALL and MCL tumor cell lines, our experiments show strong BCL2-dependent synergy between huXBR1-402-G5-PNU and venetoclax, suggesting that combined therapy should be further investigated in the clinic setting. Synergy between anthracyclines and BCL2 inhibitors is not surprising given that high BCL2 expression in early pre-B cells renders ALL cells more resistant to apoptosis induced by g-irradiation-mediated DNA damage.…”

Section: Discussionmentioning

confidence: 84%

“…[36][37][38] Venetoclax, a BH3 mimetic, inhibits the antiapoptotic actions of BCL2 and is currently in trials for both MCL and pre-B-ALL after showing promising preclinical efficacy. [39][40][41][42] Moreover, studies in triple-negative breast cancer have shown that BCL2 levels are an important indicator for response to anthracycline therapy, with tumors with lower BCL2 expression more responsive to anthracyclines. 43,44 We therefore hypothesized that a combination of huXBR1-402-G5-PNU and venetoclax would show synergy and could be used to simultaneously target both proliferative and antiapoptotic tumor niches in ROR1 1 tumors.…”

Section: Huxbr1-402-g5-pnu Synergizes With Abt-199 (Venetoclax) In a Bcl2-dependent Mannermentioning

confidence: 99%

The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia

Goswami³

et al. 2021

Blood Advances

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Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody–based therapies. Herein we describe a humanized, first-in-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR1+ malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR1+ leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR1+ hematologic malignancies.

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Safety and Efficacy of the BCL Inhibitors Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Cited by 9 publications

References 2 publications

Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies

Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies

The redox-senescence axis and its therapeutic targeting

The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia

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