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Making a Mark, a program of art and creative writing by children touched by cancer
 

 

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Baylor College of Medicine

In this issue

Director's Corner by David G. Poplack, M.D.

New Therapies in Pediatric Cancer
by Stacey Berg, M.D.

Ependymoma: A Review
by Patricia Baxter, M.D. and Murali Chintagumpala, M.D.

HIV-Related Malignancies
by Parth Mehta, M.D. and Brigitta U. Mueller, M.D.

Nasopharyngeal Carcinoma
by Chrystal U. Louis, M.D., M.P.H., Helen E. Heslop, M.D. and
Stephen Gottschalk, M.D.
 
 

New Therapies in Pediatric Cancer
by Stacey Berg, M.D.

 

Although the success rate in treatment of most childhood cancers has increased steadily over the past 40 years, not all childhood cancers are curable with current therapy. The development of new drugs for pediatric cancers therefore remains a critical component of cancer research. For many years, the mainstay of cancer therapy has been cytotoxic drugs, meaning agents that kill tumor cells and normal cells alike, usually by interfering with cell replication. The trend in newer therapies currently under development is to attempt to identify agents that are more tumor specific and less toxic to normal cells. This type of therapy is sometimes referred to as “targeted” therapy, although the accuracy of the targeting is usually imperfect. This article will highlight some of the new agents currently under investigation for treatment of children with refractory or recurrent cancer.

Small molecules
A number of small molecules that inhibit various critical processes in malignant cells are undergoing early phase studies in children.

Dasatinib
The tyrosine kinase inhibitor imatinib is the prototypic molecularly targeted drug, with highly specific activity against the BCR-ABL fusion kinase characteristic of chronic myelogenous leukemia. Dasatinib is a similar agent that retains activity against imatinib-resistant CML cells, and also has inhibitory activity against the SRC kinase. In vitro, imatinib exhibits antitumor activity against a broad spectrum of tumor types, including prostate, colon, and lung carcinomas and rhabdomyosarcoma. It is currently being studied in children with solid tumors or imatinib-resistant leukemia. 1-3

Bortezomib
The ubiquitin-proteasome pathway controls the degradation of many cell cycle regulatory proteins. Bortezomib (Velcade; PS341) inhibits the 26S proteasome, resulting in stabilization of a wide variety of proteins, including the cyclin-dependant kinase inhibitors p21 and p27 and the tumor suppressor p53. In addition, bortezomib can inhibit the antiapoptotic activity of NF-κB and bcl-2, resulting in sensitization of malignant cells to chemotherapy. Bortezomib has demonstrated activity in adults with multiple myeloma, and its role in Hodgkin’s disease in children is currently under evaluation.4-6

Lestaurtanib
FLT3 tyrosine kinase signaling is an important pathway in acute myeloid leukemia (AML). Constitutive FLT3 activation by internal tandem duplication or point mutation is commonly found in AML blasts and is associated with a poor prognosis. Lestaurtanib (CEP-701) is an orally available FLT3 inhibitor that is particularly active in AML blasts with FLT3 mutations. Lestaurtanib also appears to be synergistic in vitro with commonly used agents such as daunorubicin, etoposide, mitoxantrone and cytarabine. Because lestaurtanib also inhibits trkB, this agent is being studied in neuroblastoma in addition to leukemia.7-10

Lapatinib
Lapatinib is a dual tyrosine kinase inhibitor that has activity against both the epidermal growth factor receptor (EGFR, ErbB-1) and Her2 (ErbB-2) pathways. It shows significant clinical activity in breast cancer. Because the related tyrosine kinase ErbB-4 is present and associated with poor outcome in patients with medulloblastoma and ependymoma, lapatinib is being studied as a potential treatment in these pediatric malignancies.11-13

Ispinesib
The kinesin spindle protein (KSP) is involved in centrosome separation and the formation of mitotic spindles. KSP inhibition leads to mitotic arrest and apoptosis. In contrast to tubulin (the target of vinca alkaloids and taxanes), which performs critical functions throughout the cell cycle, KSPs are only active during mitosis. Thus, KSP inhibitors should be specific for cycling cells and are expected to be non-crossresistant with other microtubule inhibitors, for which the mechanism of resistance is often related to tubulin mutation. Ispinesib is a highly selective KSP inhibitor that is in the early stages of development in adults and children. 14,15

Histone deacetylase inhibitors
Histone proteins make up an important part of the chromatin structure. Histone acetylation (by histone acetyl transferase, HAT) and deacetylation (by histone deacetylase, HDAC) influences gene expression. HDAC inhibitors can increase expression of genes downregulated in tumors, thus decreasing tumor cell survival. HDAC inhibitors demonstrate activity against a number of pediatric tumor cell lines, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, neuroblastoma, and Ewings sarcoma. A number of HDAC inhibitors are currently being studied in children.16-19

Vorinostat (Suberoylanilide hydroxamic acid, SAHA) is an HDAC inhibitor that upregulates proapoptotic gene transcription and inhibits tumor growth in in vitro and in vivo model systems and has demonstrated clinical activities in a number of hematologic malignancies. Valproic acid, though long used as an antiepileptic drug, has more recently also been identified as an antitumor agent with HDAC inhibition as a potential mechanism of action. In preclinical models, VPA demonstrates activity against human leukemia cell lines, gliomas, neuroblastomas, and breast and other solid tumors. Both SAHA and valproic acid are undergoing early phase studies in children. 20, 21, 22, 23-28

Monoclonal antibodies
Monoclonal antibodies target cancer cells by binding to receptors or other targets that are only expressed on the tumor cells, or that are involved in pathways critical to tumor cell survival. A number of monoclonal antibodies have been approved for use in patients with cancer, including trastuzumab (Herceptin) an anti-Her2/neu antibody used in the treatment of breast cancer; rituximab, a human-murine anti-CD20 antibody used in the treatment of non-Hodgkin’s lymphoma; gemtuzumab ozogamicin (Mylotarg), an immunotoxin consisting of humanized anti-CD33 and calicheamicin for the treatment of AML; alemtuzumab (Campath-1H), an anti-CD52 monoclonal antibody used in chronic lymphoid leukemia; and ibritumomab tiuxetan (Zevalin), an immunoconjugate of murine anti-CD20 linked to Indium-111 or Yttrium-90.29-39

A number of the monoclonal antibodies that target white blood cell antigens are being developed for use in the treatment of pediatric leukemias or lymphomas. For example, a pilot study of epratuzumab alone and in combination with chemotherapy was recently conducted in children with recurrent CD22-positive acute lymphoblastic leukemia. In contrast, there are no clearly defined roles as yet for monoclonal antibodies in pediatric solid tumors. The most advanced development has been in the treatment of neuroblastoma. These tumors express a potential target in the GD2 disialoganglioside. Ch14.18 consists of a human anti-GD2 antibody linked to interleukin-2. A phase 1 study of this antibody in children has been completed; the dose limiting toxicities were hypotension, hematologic toxicity, and allergic reactions. Tumor pain was also observed. A randomized study in children with high-risk neuroblastoma to compare treatment with retinoic acid alone vs. retinoic acid in combination with immunotherapy incorporating Ch14.18 is currently underway. 40, 41

Her2 expression has been demonstrated in osteosarcoma and Ewing’s sarcoma, and overexpression may be a poor prognostic sign. These observations led to the hypothesis that the humanized anti-Her2 antibody trastuzumab (Herceptin) could have a role in the treatment of pediatric malignancy. Disappointingly, however, in vitro studies have failed to demonstrate activity of trastuzumab in osteosarcoma or Ewing’s sarcoma cell lines, even though trastuzumab shows marked activity as a single agent and in combination in Her2 positive breast cancer. 42-44

Angiogenesis inhibitors
Angiogenesis is a complex process that provides numerous potential targets for anticancer agents. Vascular endothelial growth factor (VEGF) and its receptor are critical in endothelial cell proliferation. Platelet derived growth factor (PDGF) and its receptor and the epidermal growth factor receptor (EGFR) are also important in vascular proliferation. Binding of ligand to receptor leads to induction of multiple downstream signal transduction pathways, including those involved in angiogenesis such as Ras and Raf. Agents that interfere in these pathways are collectively referred to as angiogenesis inhibitors. 45

Sorafinib and Sunitinib
Sorafinib is a Ras kinase inhibitor that also inhibits a number of receptor tyrosine kinases. This inhibitory activity interferes with signaling in the EGF, VEGF and PDGF pathways. This agent is FDA approved for the treatment of advanced renal cell cancer. Interestingly, a unique clinical trial design known as a randomized discontinuation trial was critical in the identification of Sorafanib’s activity 46. Sorafinib’s primary toxicities in adults include skin rash, palmar-plantar dysethesia, diarrhea, and fatigue. As with other angiogenesis inhibitors, hypertension is also a common side effect.45, 47 Sunitinib also inhibits a number of receptor tyrosine kinases, including VEGF-R, PDGF-R, and c-kit, and is also approved for the treatment of advanced renal cancer. Fatigue, hypertension, and skin toxicity are relatively common with this agent. In addition, decreased left ventricular ejection fraction has been noted. 45 These agents undergoing early phase trials in children.

Bevacizamab
Bevacizamab (Avastin) is a humanized anti-VEGF antibody that has demonstrated activity against a number of human cancers, especially when combined with cytotoxic agents. 48 It is approved for first-line treatment of colorectal carcinoma in combination with fluorouracil-based chemotherapy. Among the serious adverse events associated with bevacizumab administration are gastrointestinal perforation, wound healing complications and hypertension. The combination of bevacizumab with irinotecan has shown activity in high-grade gliomas and glioblastoma multiforme, a tumor family notoriously resistant to chemotherapy. 49, 50 Studies of this combination in children with brain tumors, as well as studies of bevacizumab in other solid tumors, are underway.

Summary
A number of new agents are currently being evaluated in pediatric malignancies. The trend towards development of targeted agents is likely to continue as the molcular basis of cancer is futher elucidated.

About the Author
Dr. Stacey Berg's primary area of interest is pharmacology and experimental therapeutics, with a special emphasis on the development of new anticancer drugs for children. She also has a strong interest in clinical trial design and biomedical ethics. Berg is a professor of pediatrics at Baylor College of Medicine and the Associate Dean for Research at Baylor College of Medicine.

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