The Emerging Role of Targeted Therapy for Hematologic Malignancies: Update on Bortezomib and Tipifarnib

Abstract

LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Discuss the role of bortezomib and tipifarnib in managing hematologic malignancies.2. Identify the molecular targets and mechanisms of action of bortezomib and tipifarnib.3. Describe the toxicities seen with bortezomib and tipifarnib.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTAs therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients. Bortezomib and tipifarnib are two new, targeted treatments for hematologic malignancies. Bortezomib, a proteasome inhibitor, has shown impressive efficacy in patients with relapsed multiple myeloma and as initial treatment, including before autologous stem cell transplantation. It has been studied as monotherapy and in combination with standard treatments such as dexamethasone, and with newer agents such as the immunomodulators thalidomide and lenalidomide; response is encouraging, even in patients who have relapsed after previously receiving components of a regimen as single agents. Bortezomib is generally well tolerated, including in combination with novel and conventional agents. Tipifarnib is a specific inhibitor of farnesyltransferase. Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib. Continued investigation with these new, targeted treatments will further define their use as treatment options in patients with hematologic cancer.

Therapeutic Antitumor Efficacy of Anti-CD137 Agonistic Monoclonal Antibody in Mouse Models of Myeloma

“…Currently, the two most efficacious treatment options for patients with MM are tandem high-dose chemotherapy followed by autologous stem cell infusion, or allogeneic haematopoietic stem cell transplantation after myeloablative therapy or reduced-intensity conditioning (1, 2). New drugs have recently been incorporated in our armamentarium including the proteasome inhibitor bortezomib (Velcade) (3) and thalidomide derivatives that act as immunomodulators (4). Nevertheless, cure is very rarely achieved, due to persistence of residual disease.…”

Targeting the Mevalonate Pathway for Improved Anticancer Therapy

“…Otherwise, as tipifarnib showed synergistic effects with tamoxifen on breast cancer cells [100], FTI are under investigation regarding their usefulness in the treatment of breast cancer now [101], in particular in combination with antihormonal-based therapy [102,103]. Apart from breast cancer cells, hematological malignancies such as acute myeloid leukemia (AML) also seem to respond well to tipifarnib [104][105][106][107][108]. Interestingly, tipifarnib might not be useful for cancer treatment only.…”

Never Say Die: Survival Signaling in Large Granular Lymphocyte Leukemia

“…Zarnestra is being investigated as a potential treatment in various tumors including leukemia. 38 Since Ras isoforms such as H-Ras requires farnesylation for malignant transformation activity, 39 it was hypothesized that by inhibiting farnesylation of Ras, Zarnestra would inhibit Ras-mediated signaling in LGL leukemia. A clinical trial was conducted on eight LGL leukemia patients using this drug.…”