SOHO State of the Art Updates and Next Questions | Beyond BCL-2 Inhibition in Acute Myeloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway

Maiti, Abhishek; Carter, Bing Z.; Andreeff, Michael; Konopleva, Marina

doi:10.1016/j.clml.2022.04.001

Cited by 12 publications

(9 citation statements)

References 77 publications

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“…Besides VEN, several newly developed BCL-2 inhibitors are currently in various stages of investigation in AML and other leukemia models [ Table 2 ] [ 13 , 57 - 60 ] . In addition to BCL-2, other members of the BCL-2 family of antiapoptotic proteins (MCL-1, BCL-XL, BFL-1) are the target of small molecules with the goal of inducing BAK/BAX activation and promote intrinsic apoptosis.…”

Section: Rcd Inducers In Amlmentioning

confidence: 99%

“…Agonists of the TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4/5) have been tested in AML, but response rates are low [ 13 ] . Novel antibodies against TRAILR1 and TRAILR2 have shown promising preclinical data along with synergy with VEN and are currently tested in phase 1 [ Table 2 ] [ 89 ] .…”

Section: Rcd Inducers In Amlmentioning

confidence: 99%

“…In addition, half of the patients have relapsed by 18 months and no plateau is seen on overall survival curves. In the population of VEN-AZA refractory or relapsed patients, response rate and overall survival are poor (20% and 2.4 months, respectively) [ 12 , 13 ] . The combination of VEN with ICT is also associated with high response, but 3% to 15% of patients do not respond to the treatment [ 14 ] .…”

Section: Introductionmentioning

confidence: 99%

“…Altogether, these data show that targeting RCD is a valuable strategy and has already improved the efficacy of the current AML therapeutic strategies. However, there is a real need to develop new drugs to go beyond BCL2 inhibition in AML [ 13 ] . In this review, we will discuss the main RCD pathways, describe their therapeutic targeting and discuss the main challenges for translating preclinical results into the clinic.…”

Section: Introductionmentioning

confidence: 99%

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Targeting regulated cell death pathways in acute myeloid leukemia

Garciaz¹,

Miller²,

Collette³

et al. 2023

Cancer Drug Resist

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The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.

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Section: Rcd Inducers In Amlmentioning

confidence: 99%

Section: Rcd Inducers In Amlmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting regulated cell death pathways in acute myeloid leukemia

Garciaz¹,

Miller²,

Collette³

et al. 2023

Cancer Drug Resist

View full text Add to dashboard Cite

show abstract

“…Unfortunately, patients who progress following treatment with a combination of venetoclax and azacitidine have dismal outcomes [ 15 ]. While direct MCL-1 inhibitors are currently not available for routine use in clinical practice, indirect inhibition with FLT3i offers an attractive approach to overcoming MCL-1 mediated venetoclax resistance due to the downregulation of MCL-1 [ 16 ]. Antileukemic synergistic effects of FLT3i and venetoclax are currently being evaluated in several clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

Fedorov

Maiti

Konopleva

2023

Cancers

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FLT3 mutations are present in 30% of newly diagnosed patients with acute myeloid leukemia. Two broad categories of FLT3 mutations are ITD and TKD, with the former having substantial clinical significance. Patients with FLT3-ITD mutation present with a higher disease burden and have inferior overall survival, due to high relapse rates after achieving remission. The development of targeted therapies with FLT3 inhibitors over the past decade has substantially improved clinical outcomes. Currently, two FLT3 inhibitors are approved for use in patients with acute myeloid leukemia: midostaurin in the frontline setting, in combination with intensive chemotherapy; and gilteritinib as monotherapy in the relapsed refractory setting. The addition of FLT3 inhibitors to hypomethylating agents and venetoclax offers superior responses in several completed and ongoing studies, with encouraging preliminary data. However, responses to FLT3 inhibitors are of limited duration due to the emergence of resistance. A protective environment within the bone marrow makes eradication of FLT3mut leukemic cells difficult, while prior exposure to FLT3 inhibitors leads to the development of alternative FLT3 mutations as well as activating mutations in downstream signaling, promoting resistance to currently available therapies. Multiple novel therapeutic strategies are under investigation, including BCL-2, menin, and MERTK inhibitors, as well as FLT3-directed BiTEs and CAR-T therapy.

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Venetoclax: A New Partner in the Novel Treatment Era for Acute Myeloid Leukemia and Myelodysplastic Syndrome

et al. 2023

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Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are two closely related blood cancers that are more frequent in older adults. AML is the most common type of adult acute leukemia, and MDS is characterized by ineffective blood cell production and abnormalities in the bone marrow and blood. Both can be resistant to treatment, often due to dysfunction in the process of apoptosis, the body’s natural mechanism for cell death. Venetoclax, an orally-administered medication that selectively targets the BCL-2 protein, has shown promise in enhancing treatment sensitivity in some hematological malignancies by reducing the apoptotic threshold. This review aims to evaluate the effectiveness of venetoclax in treating AML and MDS, as well as potential mechanisms of resistance to the medication. Methods A literature search was conducted utilizing PUBMED to capture all relevant research articles on the use of venetoclax as a therapy for both diseases. The MeSH terms “acute myeloid leukemia”, “myelodysplastic syndrome” and “venetoclax” were searched. Furthermore, Clinicaltrials.gov was accessed to ensure the inclusion of all ongoing clinical trials. Results Although Venetoclax showed modest results as a single-agent therapy in AML, venetoclax-based combination therapies? mainly with hypomethylating agents or low-dose cytarabine? yielded significantly positive results. Preliminary results oN the use of venetoclax-based combination therapy with HMA, mainly azacitidine, in unfit high-risk MDS also yielded optimistic results. Identification of mutations for which various drugs have been approved has spurred active investigation of venetoclax in combination trials. Conclusion Venetoclax-based combination therapies have been shown to induce rapid responses and increase overall survival in AML patients unfit for intensive chemotherapy. These therapies are also yielding positive preliminary results in high-risk MDS patients in phase I trials. Resistance to venetoclax and drug-related toxicity are two main obstacles that need to be overcome to reap the full benefits of this therapy.

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SOHO State of the Art Updates and Next Questions | Beyond BCL-2 Inhibition in Acute Myeloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway

Cited by 12 publications

References 77 publications

Targeting regulated cell death pathways in acute myeloid leukemia

Targeting regulated cell death pathways in acute myeloid leukemia

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

Venetoclax: A New Partner in the Novel Treatment Era for Acute Myeloid Leukemia and Myelodysplastic Syndrome

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