News From The Journal Of The National Cancer Institute, August 26 2008

Main Category: Cancer / Oncology
Also Included In: Biology / Biochemistry;  Clinical Trials / Drug Trials;  Genetics
Article Date: 28 Aug 2008 - 3:00 PDT

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Novel Trial Design Aims to Speed Drug Development

Researchers propose a novel multi-arm trial design that can test several therapies simultaneously and could speed drug development in cancer.

Scientists have gained important insights into the biological underpinnings of cancer, but this knowledge has not led to a jump in the number of therapies approved for clinical use. One possible reason for the slower than expected progress is the time required for clinical testing with current trial designs.

With that issue in mind, Mahesh Parmar, Ph.D., of the Medical Research Council Clinical Trials Unit in London and colleagues modified standard clinical trial methodology so that multiple therapies or combinations can be compared in a single trial. The new design incorporates standard phase II and phase III goals into one multi-phase trial and requires fewer patients than standard trials.

In the commentary, Parmar and colleagues discuss the need for fresh approaches to clinical trials, describe the new trial design in detail, and provide examples of on-going trials that use the multi-arm trial approach. "With three real examples, we hope that we have shown that such trials are feasible and can lead to major improvements in speed and decision making," the authors write.

Natural Chemical from Sea Sponges Induces Death in Cancer Cells via Unusual Pathway

A chemical called candidaspongiolide (CAN) inhibits protein synthesis but also kills cancer cells by triggering caspase 12-dependent programmed cell death.

Previous reports showed that CAN preferentially killed glioma and melanoma cells in vitro, but its mechanism of action was unknown.

In the current study, Giovanni Melillo, M.D., of the National Cancer Institute in Frederick, Md., and colleagues used molecular and cell assays to uncover the mechanism by which CAN kills cancer cells in vitro.

CAN halts protein synthesis in both normal and cancer cells but does not kill normal cells at dosages that trigger cell death in the malignant cells. CAN induces cell death by activating caspase 12 by an unusual biochemical pathway.

The investigators conclude that further tests with CAN are warranted in vitro and in animal models.

Deletion of Chromatin Remodeling Genes Leads to Leukemia in Mice

Mice lacking both copies of the Arid4A gene and one copy of the Arid4B gene develop acute myeloid leukemia (AML) and may provide an important animal model for preleukemic and leukemic conditions.

It is well known that genetic mutations, which alter the sequence of DNA in chromosomes, can lead to cancer. More recently, researchers have found that changes in chromatin structure and activity (epigenetic changes) can lead to cancer as well. The Arid4 family of genes is involved in chromosome remodeling, but their impact on leukemia was not known.

Arthur Beaudet, M.D., of Baylor College of Medicine in Houston and colleagues bred mice that lacked both copies of Arid4A and one copy of Arid4B. They monitored the animals' health through repeated blood cell counts and molecular tests on blood and bone marrow cells.

The mutant mice developed a myeloproliferative disorder that resembled chronic myeloid-monocytic leukemia. The animals then progressed to AML. The pattern of disease progression in the animals resembled the course of events in humans and may indicate that the mutant mice are useful models for studying how AML develops and testing potential therapeutics.

"Further study of the Arid4 gene family may advance our understanding of the connection between gene regulation, epigenetic control, disease development, and cancer formation," the authors write. "We also suggest that gene regulation by the ARID4A and ARID4B should be examined for potential disease-related roles, not only in human malignancies, but also in other complex disease traits."

Mutations in the Succinate Dehydrogenase Subunit B Gene Associated with Familial Renal Cell Cancer

Individuals who have a germline mutation in the succinate dehydrogenase subunit B (SDHB) gene presented with familial renal cell cancer (RCC) or with bilateral RCC.

Previous research suggested that germline mutations in succinate dehydrogenase genes were principally associated with the development of pheochromocytoma or paraganglioma, which are tumor syndromes that affect other tissues. Although RCC had been reported occasionally in individuals with a germline SDHB mutation, these individuals had a personal or family history of pheochromocytoma or paraganglioma. Therefore, the association of mutations in succinate dehydrogenase genes with familial RCC in the absence of other tumor syndromes was unknown.

In the current study, Eamonn Maher, M.D., of the University of Birmingham in the UK and colleagues sequenced the genes encoding several of these enzymes in 68 individuals who had either familial RCC or bilateral RCC but who showed no evidence of pheochromocytoma or paraganglioma.

They identified three individuals with germline mutations in SDHB in this population. They conclude that the mutations are associated with an increased risk of inherited RCC.

"Our findings suggest that individuals presenting with features of inherited RCC susceptibility should be screened for germ¬line SDHB mutations because surveillance for SDHB-related tumors can then be offered to mutation-positive patients and relatives," the authors write.

In an accompanying editorial, Charis Eng, M.D., Ph.D., of the Cleveland Clinic in Ohio notes that the new data confirm previous reports of an association between mutations in the SDHB gene and familial RCC. She thinks, however, that it is too early to conclude whether such mutations occur in the absence of tumor syndromes given the relatively young age at which the three patients in Maher's study either died or were lost to follow-up and the later age of onset for pheochromocytoma or paraganglioma.

Nonetheless, the new data have clinical utility, according to Eng. "It is entirely appropriate, at this time, to counsel patients carrying SDHB mutations, espe¬cially those with Arg mutations, that they have a small but finite likelihood of developing RCC," she writes.

Also in the August 26 JNCI:

* http://www.eurekalert.org/emb_releases/2008-08/jotn-aia082108.php

* http://www.eurekalert.org/emb_releases/2008-08/jotn-hon082108.php

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Article adapted by Medical News Today from original press release.
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The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Visit the Journal online at http://jnci.oxfordjournals.org/.

Source: Liz Savage
Journal of the National Cancer Institute