Targeting BCL2 in Chronic Lymphocytic Leukemia and Other Hematologic Malignancies

Yalniz, Fevzi F.; Wierda, William G.

doi:10.1007/s40265-019-01163-4

Cited by 28 publications

(17 citation statements)

References 139 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Early trials however were halted due to the emergence of a rapid onset of tumor lysis syndrome where rapidly dying cancer cells release their contents into the blood often having fatal consequences. Altering the scheduling of venetoclax, using a ramp up approach, combined with careful clinical monitoring of patients, resulted in durable clinical responses, with venetoclax subsequently gaining FDA breakthrough therapy designation in 2015 and approval for the treatment of CLL in 2016 for del(17p) CLL patients [ 33 , 34 , 35 ]. In addition, venetoclax received accelerated approval for use in combination with either azacytidine, decitabine or cytarabine for AML patients ineligible for intensive induction chemotherapy [ 36 ].…”

Section: Therapeutic Strategies For Promoting Apoptosis Directly—intrinsic Pathwaymentioning

confidence: 99%

Therapeutics Targeting the Core Apoptotic Machinery

Hamilton

Fox

Longley

et al. 2021

Cancers

View full text Add to dashboard Cite

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.

show abstract

Section: Therapeutic Strategies For Promoting Apoptosis Directly—intrinsic Pathwaymentioning

confidence: 99%

Therapeutics Targeting the Core Apoptotic Machinery

Hamilton

Fox

Longley

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…518 S64315 (MIK665), another MCL-1 inhibitor derived from S63845, can induce apoptosis in diverse hematological malignancies in a Bax/Bak-dependent manner. 519 It is undergoing evaluation in several phase I clinical trials in patients with relapsed/refractory AML or MDS (NCT02979366), and relapsed/refractory MM or lymphoma (NCT02992483). Two other MCL-1 inhibitors AZD-5991 520 and AMG-176 521 have also entered clinical trials to evaluate their safety, PKs, and antitumor response in patients with hematological malignancies (NCT03218683 and NCT02675452).…”

Section: Bcl-2 Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

962

490

View full text Add to dashboard Cite

Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

show abstract

“…Preclinical and clinical studies have demonstrated that the selective and highly potent BCL-2 inhibitor ABT-199 (venetoclax), has antileukemia activities against various hematologic malignancies, including MDS, CLL, and AML (14)(15)(16)(17). ABT-199 is FDA approved for a subset of patients with CLL and AML (18,19). Although ABT-199 demonstrated strong antileukemia activity preclinically (17), as a single agent it has shown limited clinical efficacy in AML (14).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia

Wang

Mak

et al. 2020

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Focal adhesion kinase (FAK) promotes cancer cell growth and metastasis. We previously reported that FAK inhibition by the selective inhibitor VS-4718 exerted antileukemia activities in acute myeloid leukemia (AML). The mechanisms involved, and whether VS-4718 potentiates efficacy of other therapeutic agents, have not been investigated. Resistance to apoptosis inducted by the BCL-2 inhibitor in AML is mediated by preexisting and ABT-199-induced overexpression of MCL-1 and BCL-XL. We observed that VS-4718 or silencing FAK with siRNA decreased MCL-1 and BCL-XL levels. Importantly, VS-4718 antagonized ABT-199-induced MCL-1 and BCL-XL. VS-4718 markedly synergized with ABT-199 to induce apoptosis in AML cells, including primary AML CD34 þ cells and AML cells overexpressing MCL-1 or BCL-XL. In a patient-derived xenograft (PDX) model derived from a patient sample with NPM1/FLT3-ITD/TET2/DNMT3A/WT1 mutations and complex karyotype, VS-4718 statistically significantly reduced leukemia tissue infiltration and extended survival (72 vs. control 36 days, P ¼ 0.0002), and only its combination with ABT-199 effectively decreased systemic leukemia tissue infiltration and circulating blasts, and prolonged survival (65.5 vs. control 36 days, P ¼ 0.0119). Furthermore, the combination decreased NFkB signaling and induced the expression of IFN genes in vivo. The combination also markedly extended survival of a second PDX model developed from an aggressive, TP53-mutated complex karyotype AML sample. The data suggest that the combined inhibition of FAK and BCL-2 enhances antileukemia activity in AML at least in part by suppressing MCL-1 and BCL-XL and that this combination may be effective in AML with TP53 and other mutations, and thus benefit patients with high-risk AML.

show abstract

Targeting BCL2 in Chronic Lymphocytic Leukemia and Other Hematologic Malignancies

Cited by 28 publications

References 139 publications

Therapeutics Targeting the Core Apoptotic Machinery

Therapeutics Targeting the Core Apoptotic Machinery

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia

Contact Info

Product

Resources

About