June 15, 2008 (Vol. 28, No. 12)

An Optimistic View of Targeting Specific Pathways, Epigenetics, and Cancer Stem Cells

The “Annual Meeting for the American Association for Cancer Research (AACR)” is widely viewed by scientists as the main forum to present and discuss cancer-related research. In the past, most of the symposia and sessions at this meeting have focused on topics such as angiogenesis of solid tumors, oncogenes and tumor suppressor genes, the molecular pathways giving rise to transformed cells, metastasis of highly aggressive cancers, and cancer stem cells.

At this year’s meeting, however, it was apparent that the delineation of new molecular pathways and regulation of gene expression have led to the development of anticancer agents that can block the signaling pathways that regulate gene expression in malignant cells. Quite a few researchers presented preclinical and early Phase I/II results for new drugs targeting various signaling pathways that cause malignant cells to lose their hyperproliferative state and exit the cell cycle.

There are many anticancer drugs under development that target Hedgehog and Wnt signaling as well as epigenetic modifications in cancer cells. Drug developers are optimistic that this new class of cancer drugs will be more effective in killing malignant cells and, more importantly, targeting quiescent cancer stem cells that may become activated by current anticancer regimens.

Hedgehog Signaling Inhibitor

Genentech (www.gene.com) currently has a drug in the clinic that inhibits Hedgehog signaling in neoplastic cells. Developed in collaboration with Curis (www.curis.com), GDC-0449 is an orally bioavailable small molecule that antagonizes the Smoothened receptor involved in the Hedgehog signaling pathway.

GDC-0449 is a derivate of cyclopamine, a natural compound found in wild corn lily. Cyclopamine is a teratogen and its discovery was based on the observation that pregnant ewes grazing on the wild corn lily produced cyclopic offspring.

Last year at the AACR meeting, researchers from Johns Hopkins presented data revealing that cyclopamine inhibited glioblastoma multiforme growth by antagonizing the Smoothened receptor. The investigators found that malignant cells treated with cyclopamine downregulated the expression of Gli1—a nuclear protein whose presence is associated with Hedgehog signaling.

Hedgehog signaling is a key regulator of both insect and animal development. In mammals, the pathway is involved in regulating the fate of progenitor cells. Many cancer researchers believe that aberrant Hedgehog signaling can give rise to a malignant population of cancer stem cells.

The pathway involves two receptors, Patched and Smoothened. When the Patched receptor is not bound to its sonic Hedgehog ligand, it prevents the expression and activity of Smoothened. A majority of aberrant Hedgehog signaling in cancer cells is a result of a mutation in the Patched receptor (90%). A mutated Patched receptor results in Smoothened being in an activated state, which causes constant Hedgehog signaling and, thus, the hyperproliferative state of malignant cells.

James C. Marsters, Ph.D., a scientist at Genentech, noted in his presentation that GDC-0449 was found to be 10 times more potent than cylopamine in antagonizing Smoothened’s activity.

Daniel D. Von Hoff, M.D., from TGen (www.tgen.com), presented preliminary Phase I results involving GDC-0449 for the treatment of nine patients with locally advanced or metastatic basal cell carcinoma. In a dose-escalation open-label study, the patients were administered various doses of the drug (either 150, 270, or 540 mg/day) once a day. Dr. Von Hoff noted that over a long duration of therapy, there were mild toxicities associated with the drug (loss of hair and weight loss), but it was generally well tolerated.

One of the nine patients had tumor progression and died, while the remaining eight patients demonstrated tumor regression and remained in the study for 128–148 days. Tissue biopsies from patients revealed a downregulation of Gli1 expression, which demonstrated that the drug was having an effect on blocking Hedgehog signaling concomitant with tumor regression.

Interestingly, although there were over one million cases of metastatic basal cell carcinoma reported in the U.S. in 2008, it is still classified as a rare disease. Ninety percent of the metastatic disease has a Patched mutation, which most likely gives rise to cancer stem cells. If Genentech is able to obtain orphan drug approval from the FDA, GDC-0449 may have the potential to become a blockbuster drug as a first-line therapy for treating cancers.

Histone Deacetylase Inhibitors

In the last few years, there has been a plethora of research focused on epigenetic modification of the chromatin within a cell’s genome. These changes appear to regulate differentiation of stem cells as well as give rise to malignant cells. Much of the research has focused on enzymatic reactions involving deacetylation of histone.

Recent data has shown that histone modifications may serve as chemical switches for regulating gene expression. Since histone deacetylase (HDAC) is known to have increased activity in cancer cells due to its ability to repress tumor suppressor gene expression, there is mounting evidence that these altered epigenetic changes are involved in the development of cancer. Thus, inhibitors of HDAC are now being explored as new drug targets for treating cancer.

Pharmacyclics (www.pharmacyclics.com) is currently in a Phase I trial with its HDAC inhibitor (HDACI), PCI-24781, an oral broad-spectrum HDACI for treating both solid and hematologic malignancies.

Sriram Balasubramanian, director of translational research at Pharmacyclics, presented data delineating the mechanisms by which PCI-24781 induces cell-cycle arrest and upregulates death receptors. Ultimately, the drug induces the production of caspases, which results in apoptosis in neoplastic cells.

Abbott Laboratories (www.abbott.com) is also developing an anticancer drug, ABT-737, which synergistically acts with HDAC inhibitors in promoting apoptosis in malignant cells. ABT-737 is an antagonist that inhibits the expression of the proapoptotic Bcl-2 gene with demonstrated efficacy in killing malignant cells. According to Shuang Chang from the Virginia Commonwealth University, HDACIs increase the expression of the proapoptotic protein, Bim, in which Bcl-2 binding to Bim neutralizes its activity. When ABT-737 is coadministered with HDACIs, however, Bim is displaced from the Bcl-2, which leads to apoptosis of the malignant cells.

From Bench to Bedside

It took over two decades from the discovery of mAbs in 1975 to the first FDA mAb approval, which was awarded to Biogen Idec (www.biogenidec.com) for Rituxan for treating non-Hodgkin’s B cell lymphomas. mAbs are now used as standard therapy for treating some leukemias.

A second generation of mAbs will soon make its way into the clinic. Micromet (www.micromet-inc.com) presented preclinical primate data on MT110, developed using its BiTE antibody technology. The company’s bispecific hybrid antibodies are made by fusing two humanized mAb fragments having different specificities.

One antibody fragment is designed to bind to a surface epitope (CD3) on T cells in order to enhance T cell-mediated killing of a targeted cancer cell. The second antibody fragment has been engineered to bind to a specific epitope of the cancer cell. The bispecific antibody acts as a bridge or immunological synapse between the T cell and the cancer cell with enhanced cytotoxic destruction of the cancer cell.

For MT110, the second antibody fragment targets an epithelial adhesion molecule, EpCAm/CD326, which is also expressed on the surface of cancer cells. Micromet presented preclinical data demonstrating that both subcutaneous and intravenous administration of MT110 resulted in 30–40% bioavailability of the drug over a six-day period.

Considering the number of investigators presenting preclinical and early clinical data at this year’s AACR meeting, the cliché “from bench to bedside” seems apropos for describing the new class of anticancer agents emanating from basic research laboratories as well as new technologies being advanced by the biotech industry. Thirty seven years after President Nixon declared war on cancer, there finally appears to be a new class of drugs that may actually cure cancer in the near future.

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