Hady Ghanem

University Medical Center Rizk Hospital

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Elias Jabbour

The University of Texas MD Anderson Cancer Center

Hagop M. Kantarjian

The University of Texas MD Anderson Cancer Center

Jorgé E. Cortes

National Cancer Center of Georgia

Farhad Ravandi

The University of Texas MD Anderson Cancer Center

Guillermo García-Manero

The University of Texas MD Anderson Cancer Center

Sherry Pierce

The University of Texas MD Anderson Cancer Center

Tapan M. Kadia

The University of Texas MD Anderson Cancer Center

Susan O’Brien

University of California, Irvine

Stefan Faderl

Jazz Pharmaceuticals (United States)

Alfonso Quintás‐Cardama

Leitat Technological Center

Cooperative Institutions

The University of Texas MD Anderson Cancer Center

Bladder Cancer Advocacy Network

Integra (United States)

Lebanese American University

American University of Beirut Medical Center

American University of Beirut

University Medical Center Rizk Hospital

Cornell University

John Wiley & Sons (United States)

Memorial Sloan Kettering Cancer Center

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Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)

Translational Oncology (2015)

Amira Bekdash Manal Darwish Zahra Timsah Elias Kassab Hady Ghanem

In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34(+) bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML.

Anthrax toxin

10.1016/j.tranon.2015.07.001

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Citations (11)

Outcome of Patients (pts) with Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure.

Blood (2012)

Elias Jabbour Naval Daver Tina T. X. Dong Tapan M. Kadia Susan O’Brien

Decitabine

Chronic myelomonocytic leukemia

Azacitidine

10.1182/blood.v120.21.2824.2824

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Clofarabine in leukemia

Expert Review of Hematology (2010)

Hady Ghanem Elias Jabbour Stefan Faderl Varsha Ghandhi William Plunkett

Clofarabine is a second-generation purine nucleoside analogue that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared with its precursors, clofarabine has an increased resistance to deamination and phosphorolysis, hence better stability, as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. In 1993, the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemia. Owing to its unique properties of biochemical modulation when used in combination with other established antileukemic drugs, mainly cytarabine, combination regimens containing clofarabine are being evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This article describes the development, pharmacology and clinical activity of clofarabine, as well as its emerging role in the treatment of acute leukemia, myelodysplastic syndrome and solid tumors.

Clofarabine

Cladribine

Deoxycytidine kinase

Nucleoside analogue

Ribonucleotide reductase

10.1586/ehm.09.70

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Citations (31)

Targeted therapy in chronic myeloid leukemia

Expert Review of Anticancer Therapy (2007)

Elias Jabbour Jorgé E. Cortes Hady Ghanem Susan O’Brien Hagop M. Kantarjian

Chronic myeloid leukemia (CML) is characterized by the formation of the Philadelphia chromosome and oncogenic signaling by the resulting Bcr-Abl fusion protein. Understanding the molecular basis of CML has led to the development of highly effective targeted therapies that block Bcr-Abl tyrosine kinase activity. Imatinib, the current first-line therapy for CML, induces durable treatment responses in most patients. However, patients may develop imatinib resistance, which is often due to BCR-ABL mutations. With the availability of second generation tyrosine kinase inhibitors, an effective therapeutic option other than stem cell transplantation is available following imatinib failure. Randomized trial data suggest that dasatinib treatment is superior to imatinib dose escalation in patients with imatinib resistance. Nilotinib, a recently approved analogue of imatinib, has also demonstrated encouraging treatment responses in patients with imatinib-resistant CML. Other agents (including bosutinib and INNO-406) are in clinical development. With the potential availability of multiple treatment options for patients with CML, it may be possible to tailor treatment according to individual patient or disease characteristics, for example, BCR-ABL mutations. Future CML treatment may involve combination strategies. Overall, targeted agents have significantly improved the prognosis of patients diagnosed with CML.

Bosutinib

Imatinib Mesylate

Targeted Therapy

Philadelphia chromosome

10.1586/14737140.8.1.99

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Citations (43)

Very High Rate of Leukemic Transformation and Poor Survival in Patients with Lower Risk Myelodysplastic Syndrome (MDS) Who Dynamically Acquire FLT3 Molecular Alteration (FLT3m): Study of 290 MDS Patients with Sequential Mutation Analysis

Blood (2012)

Koichi Takahashi Elias Jabbour Xuemei Wang Hady Ghanem Naveen Pemmaraju

10.1182/blood.v120.21.3802.3802

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Acute Myeloid Leukemia After Myelodysplastic Syndrome and Failure of Therapy With Hypomethylating Agents: An Emerging Entity With a Poor Prognosis

Clinical Lymphoma Myeloma & Leukemia (2013)

Elias Jabbour Hady Ghanem Xuelin Huang Farhad Ravandi Guillermo Garcia‐Manero

Hypomethylating agent

Azacitidine

10.1016/j.clml.2013.10.013

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Citations (14)

Acute Myeloid Leukemia (AML) Following Myelodysplastic Syndrome (MDS) and Failure of Therapy with Hypomethylating Agents (HMA): An Emerging Entity With a Poor Prognosis

Clinical Lymphoma Myeloma & Leukemia (2013)

Hady Ghanem Elias Jabbour Xuelin Huang Farhad Ravandi Guillermo Garcia‐Manero

Hypomethylating agent

Decitabine

Azacitidine

10.1016/j.clml.2013.07.087

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Renal cell carcinoma management: real-world practice and challenges at a national level

Future Oncology (2023)

Marwan Ghosn Joseph Kattan Fadi El Karak Hady Ghanem Jamil Debs

Renal cell carcinoma (RCC) management has seen a revolution over the last decades. Six Lebanese oncologists discussed recent updates in RCC management and outlined the challenges and future directions in Lebanon. Sunitinib continues to be a first-line choice for metastatic RCC in Lebanon, except for intermediate- and poor-risk patients. Immunotherapy is not always accessible to patients or selected routinely as first-line therapy. More data are needed on the sequencing of immunotherapy and tyrosine kinase inhibitor treatments and on the use of immunotherapy beyond progression and/or after failure of immunotherapy in the first-line setting. For second-line management, the clinical experience with axitinib for low tumor growth rate and nivolumab after progression on tyrosine kinase inhibitors make those two agents the most widely used. Several challenges affect the Lebanese practice, limiting the accessibility and availability of the medications. Reimbursement remains the most critical challenge, especially with the socioeconomic crisis of October 2019.

Axitinib

Reimbursement

10.2217/fon-2021-1189

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Citations (3)

Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) After Surviving 5 Years of Initial Therapy with Interferon Alpha (IFN), Imatinib (IMA) or Allogeneic Stem Cell Transplantation (ASCT)

Blood (2012)

Hady Ghanem Hagop M. Kantarjian Richard E. Champlin Lakshmikanth Katragadda Gabriela Rondón

Imatinib Mesylate

10.1182/blood.v120.21.2001.2001

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Composite Hodgkin and Non-Hodgkin Lymphomas: Report of Two Cases with Unusual Presentations

Journal of Blood & Lymph (2017)

Rami Nassabein Siham Fleifel Noha Bejjani Hady Ghanem Dany Abi Gerges

Composite lymphoma is a rare entity of lymphoma where two types of lymphoma are present synchronously. We recently encountered two cases of composite lymphomas that are not rare in the morphology and pathology only, but also rare in the site of involvement and presentation. In this report we present a case of composite lymphoma that presented as primary splenic lymphoma, the second case presented with GI symptoms due to its presence in the colon.

10.4172/2165-7831.1000180

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Citations (2)