Zhihong Zeng

The University of Texas MD Anderson Cancer Center

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Marina Konopleva

Albert Einstein College of Medicine

Michael Andreeff

The University of Texas MD Anderson Cancer Center

Farhad Ravandi

The University of Texas MD Anderson Cancer Center

Gautam Borthakur

The University of Texas MD Anderson Cancer Center

Elias Jabbour

The University of Texas MD Anderson Cancer Center

Steven M. Kornblau

The University of Texas MD Anderson Cancer Center

Hagop M. Kantarjian

The University of Texas MD Anderson Cancer Center

Courtney D. DiNardo

The University of Texas MD Anderson Cancer Center

Francis J. Giles

Aegera Therapeutics (Canada)

Karen Yee

Princess Margaret Cancer Centre

Cooperative Institutions

The University of Texas MD Anderson Cancer Center

109

Dana-Farber Cancer Institute

The University of Texas Health Science Center at Houston

Harvard University

Leukemia Research Foundation

Moffitt Cancer Center

University of Oxford

MRC Weatherall Institute of Molecular Medicine

John Wiley & Sons (United States)

Scripps MD Anderson Cancer Center

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Decitabine-Venetoclax Treatment Reactivates Endogenous Retrovirus RNA Signaling in AML Cells and Induces T Cell Activation

Blood (2024)

Kotoko Yamatani Kaori Saito Abhishek Maiti Abdullah Khasawneh Faith Jessica Paran

Venetoclax

Decitabine

Azacitidine

Endogenous retrovirus

Aldesleukin

Interferon type II

10.1182/blood-2024-202722

Cite

Citations (0)

Dual-targeting CD33/CD123 NANOBODY® T cell engager with potent anti-AML activity and good safety profile

Blood Advances (2024)

Zhihong Zeng Annelies Roobrouck Geert Deschamps Hélène Bonnevaux S. Guérif

Abstract Novel therapies are needed for effective treatment of acute myeloid leukemia (AML). Relapse is common and salvage treatment with cytotoxic chemotherapy is rarely curative. CD123 and CD33, 2 clinically validated targets in AML, are jointly expressed on blasts and leukemic stem cells in >95% of patients with AML. However, their expression is heterogenous between subclones and between patients, which may affect the efficacy of single-targeting agents in certain patient populations. We present here a dual-targeting CD33/CD123 NANOBODY T-cell engager (CD33/CD123-TCE) that was designed to decrease the risk of relapse from possible single antigen-negative clones and to increase coverage within and across patients. CD33/CD123-TCE killed AML tumor cells expressing 1 or both antigens in vitro. Compared with single-targeting control compounds, CD33/CD123-TCE conferred equal or better ex vivo killing of AML blasts in most primary AML samples tested, suggesting a broader effectiveness across patients. In a disseminated cell-line–derived xenograft mouse model of AML, CD33/CD123-TCE cleared cancer cells in long bones and in soft tissues. As cytokine release syndrome is a well-documented adverse effect of TCE, the compound was tested in a cytokine release assay and shown to induce less cytokines compared to a CD123 single-targeting control. In an exploratory single-dose nonhuman primate study, CD33/CD123-TCE revealed a favorable PK profile. Depletion of CD123 and CD33 expressing cells was observed, but there were neither signs of cytokine release syndrome nor clinical signs of toxicity. Taken together, the CD33/CD123 dual-targeting NANOBODY TCE exhibits potent and safe anti-AML activity and promises a broad patient coverage.

Interleukin-3 receptor

10.1182/bloodadvances.2023011858

Cite

Citations (2)

BH3 Mimetics Augment Cytotoxic T Cell Killing of Acute Myeloid Leukemia via Mitochondrial Apoptotic Mechanism

Research Square (Research Square) (2024)

Cassian Yee Kapil Saxena Esther Ryu Shao-Hsi Hung Shailbala Singh

Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8 + T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8 + T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, we found that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the same apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.

Augment

10.21203/rs.3.rs-5307127/v1

Cite

Citations (0)

Patterns and Prognostic Impact of PI3K-AKT Pathway Activation, Regulation and Downstream Activity in AML Using Reverse Phase Proteins Arrays (RPPA).

Blood (2007)

Steven M. Kornblau Yihua Qiu Shana L. Palla Zhihong Zeng Wenjing Chen

XIAP

Proto-Oncogene Proteins c-akt

10.1182/blood.v110.11.2393.2393

Cite

Citations (1)

Abstract 3659: The AKT inhibitor MK-2206 promotes apoptosis in acute myeloid leukemia cells

Cancer Research (2012)

Peter P. Ruvolo Zhihong Zeng Vivian Ruvolo Gautam Borthakur Steven M. Kornblau

Abstract The need for improved therapies for acute myeloid leukemia (AML) is urgent as the disease is still highly fatal. Protein Kinase B (AKT) activation has been shown to predict poor clinical outcome for patients with AML. In 253 newly diagnosed AML cases, we have found that AKT phosphorylation on Thr308 analyzed by reverse-phase protein arrays was significantly higher in patients with unfavorable cytogenetics (p=0.037). The adverse prognostic factor of high levels of pAKT was observed among patients with intermediate-risk cytogenetics (p=0.013), as it was associated with an inferior survival (median survival 44.2 weeks) compared to patients with low or intermediate pAKT (78.7 weeks). Recently, Merck Sharp & Dohme Corp. has developed a compound, MK-2206, that is a highly specific allosteric inhibitor for all three AKT isoforms. In the current study, we have determined that MK-2206 as a single agent used at clinically achievable concentrations suppresses cell growth of a variety of AML derived cell lines including OCI-AML3, U937, and MOLM13. MK-2206 can also induce apoptosis in blast cells derived from AML patients. Consistent with its role as an AKT inhibitor, the drug suppresses phosphorylation of AKT at serine 473 and inhibits phosphorylation of AKT downstream targets including S6 ribosomal protein, 4-EBP1, and PRAS40 in the AML cells. We recently identified that low expression of the PP2A isoform that acts as the AKT phosphatase (i.e. the one containing the B55α subunit) in AML negatively correlates with AKT T308 phosphorylation and activation in a cohort of 511 AML patients (Ruvolo et al Leukemia, 2011). Patients with low B55α expression exhibited shorter complete remission duration. We suppressed B55α expression by shRNA in OCI-AML3 cells to determine if loss of the AKT phosphatase promotes AKT activation and chemoresistance. Cells with reduced B55α exhibited higher levels of AKT phosphorylation and were more resistant to killing by the conventional chemotherapy agent AraC. OCI-AML3 B55α shRNA transductant cells were also more resistant to MK-2206 compared to cells expressing control non-specific shRNA. These results suggest that AKT phosphatase activity in AML may affect response to MK-2206. A recent study in liver cancer demonstrated that MK-2206 synergized with the multi-kinase inhibitor Sorafenib. Since Sorafenib targets the Fms-like tyrosine kinase 3 (FLT3) and mutations that activate the kinase in AML confer poor prognosis, we examined if MK-2206 could synergize with Sorafenib to kill leukemia cells with mutation of FLT3 internal tandem duplication (ITD) mutation. The combination of MK-2206 and Sorafenib was effective at killing MOLM13 cells and AML blast cells with the FLT3-ITD. Taken together, these findings suggest that MK-2206 may be effective to block AKT signaling pathways and could be beneficial as a therapeutic agent perhaps as a single agent or in combination with a drug such as Sorafenib in the therapy of AML. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3659. doi:1538-7445.AM2012-3659

10.1158/1538-7445.am2012-3659

Cite

Citations (0)

A Phase I/II Trial of Plerixafor/G-CSF Combined with IV Bu/Flu Conditioning Regimen In AML/MDS Patients Undergoing Allogenic Stem Cell Transplantation

Blood (2010)

Marina Konopleva Zhihong Zeng Ruiyu Wang Peter F. Thall Gloria McCormick

Plerixafor

Regimen

10.1182/blood.v116.21.2358.2358

Cite

Citations (3)

Rapamycin derivatives reduce mTORC2 signaling and inhibitAKT activation inAML

Zhihong Zeng Dos D. Sarbassov Ismael Samudio Karen Yee Mark F. Munsell

mTORC2

Source

Cite

Citations (1)

Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies

Clinical Cancer Research (2006)

Karen Yee Zhihong Zeng Marina Konopleva Srđan Verstovšek Farhad Ravandi

Abstract Purpose: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies. Experimental Design: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study. Results: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response. Conclusions: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted.

Everolimus

Mucositis

10.1158/1078-0432.ccr-06-0764

Cite

Citations (291)

Venetoclax plus low intensity chemotherapy for adults with acute lymphoblastic leukemia

Blood Advances (2024)

Marlise R. Luskin Shai Shimony Julia Keating Eric S. Winer Jacqueline S. Garcia

In acute lymphoblastic leukemia (ALL), the BCL2 inhibitor venetoclax may enhance the efficacy of chemotherapy allowing dose reductions that reduce toxicity. We designed a phase 1b study of venetoclax plus attenuated chemotherapy to determine the recommended phase 2 dose (RP2D) of venetoclax. The study enrolled 19 patients with ALL either newly diagnosed (≥60 years, n=11 [B-cell, n=8; T-cell, n=3]) or R/R (≥18 years, n=8 [B-cell, n=3; T-cell, n=5]). Venetoclax was given for 21 days with each cycle of mini-hyper-CVD (cyclophosphamide, vincristine, dexamethasone alternating with methotrexate and cytarabine). There were no dose limiting toxicities at dose level (DL) 1 (n=3, 400 mg/day) or DL2 (n=6, 600 mg/day); DL2 was the RP2D and explored further (n=10). The most common non-hematologic adverse events were grade 3+ infections. There were no deaths within 60 days and no patients discontinued therapy for toxicity. There was no tumor lysis syndrome, hepatotoxicity, or prolonged cytopenias. Among patients with newly diagnosed ALL, 10/11 (90.9%) achieved a measurable residual disease-negative (<0.01% sensitivity) complete remission (CR) including 6 patients with hypodiploid TP53 mutated ALL. All patients in CR bridged to hematopoietic stem cell transplant (n=9) or completed protocol (n=1). With a median follow-up of 60.0 months, median disease-free survival (DFS) for patients with newly diagnosed ALL was 54.6 months (95% CI: 35.5 months - NA) with a 2-year DFS rate of 90% (95% CI, 71% - 100%). Among patients with R/R ALL, 3/8 (37.5%) achieved CR. In summary, for patients with newly diagnosed ALL, venetoclax plus mini-HCVD is well-tolerated with promising efficacy. NCT03319901

Venetoclax

Minimal Residual Disease

Acute lymphocytic leukemia

10.1182/bloodadvances.2024014405

Cite

Citations (0)

Decitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial

The Lancet Haematology (2024)

Nicholas J. Short Daniel Nguyen Elias Jabbour Jayastu Senapati Zhihong Zeng

Venetoclax

Decitabine

Ponatinib

10.1016/s2352-3026(24)00250-3

Cite

Citations (2)