Tumor Antigen Project
Genentech's Tumor Antigen Project has become a major focus of the company's Molecular Oncology Department. Initially inspired by the success of Genentech's two flagship oncology products, Herceptin® (Trastuzumab), which targets the HER2 gene, and Rituxan® (Rituxumab). which targets the CD20 gene, today the project includes many different molecules that are being evaluated in a number of cancers.

Genentech scientists found that when anti-HER2 and anti-CD20 antibodies bind to the molecules on the surface of tumor cells, they could effectively and selectively kill these tumor cells. Arming the antibodies with drugs may further enhance their potency against tumor cells expressing the targeted antigen.

By taking advantage of the general principles of immunotherapy basic to the Tumor Antigen Project, Genentech scientists are currently working to discover therapeutic antibodies for other cancers, including colon, prostate, and liver cancer, as well as breast cancers that do not respond to HER2. The search involves isolating genes that are abundantly expressed on certain tumor cells and either are not expressed or expressed in lower levels on normal cells.

Angiogenesis
Angiogenesis refers to the process by which new blood vessels are formed within the body. When tissues need more oxygen, for example, they release molecules that encourage blood vessels to grow. The ability to inhibit angiogenesis and turn off the blood supply to tumors could potentially lead to a new generation of cancer therapies. Genentech scientists led by Napoleone Ferrara have been at the forefront of basic research on angiogenesis.

Ferrara and his team identified the gene for vascular endothelial growth factor (VEGF) more than 10 years ago and then characterized the VEGF protein as a major regulator of angiogenesis in a broad variety of circumstances, including embryonic development, reproductive functions and endochondral bone formation. In addition, they demonstrated that VEGF is a key mediator of tumor angiogenesis. These studies led to the development of a humanized anti-VEGF antibody, Avastin® (bevacizumab) as a therapy for solid tumors. Avastin received U.S. Food and Drug Administration approval in February 2004 for use in combination with intravenous 5-Fluorouracil-based chemotherapy as a treatment for first-line metastatic colorectal cancer. Avastin is currently in Phase III studies for several malignancies. Their studies on the role of VEGF in intraocular neovascularization also initiated clinical development of an anti-VEGF antibody fragment as a therapy for wet age-related macular degeneration, Lucentis™ (ranibizumab).

Currently, Ferrara's team is investigating mechanisms of tumor angiogenesis alternative to VEGF and novel, tissue-selective, endothelial cell mitogens. As part of this latter initiative, in August 2001, Ferrara's team isolated a molecule, which they dubbed EG-VEGF (endocrine gland vascular endothelial growth factor) that forms new blood vessels only in endocrine-system tissues. This breakthrough finding suggests that there may be ways to turn the blood supply on and off to specific parts of the body -- a finding that may have therapeutic implications not only for cancer, but heart disease, wound-healing, and blindness.

The discovery of EG-VEGF provides a model for Genentech scientists in their search for other factors, or molecules, that regulate the blood supply for other organ systems.

Apoptosis
Apoptosis is the mechanism by which cells self-destruct themselves. This natural regulatory program for suicide exists in all cells, including cancer cells, and may prove extremely valuable in fighting the disease. Under normal conditions, apoptosis serves to eliminate damaged or unneeded cells from the organism. However, in cancer cells, this self-regulation program is silenced, allowing tumors to survive and grow.

Genentech researchers Vishva Dixit and Avi Ashkenazi are leading the discovery of new ways to activate the apoptosis machinery in cancer cells as a means of attacking tumors. One such gene, discovered by the Ashkenazi lab and independently at Immunex (now Amgen), encodes a protein called Apo2L/TRAIL, which triggers apoptosis in various types of cancer cells but not in most normal cells. Unlike conventional anti-cancer agents such as chemotherapy, Apo2L/TRAIL triggers apoptosis independently of the p53 tumor suppressor gene. Since more than half of human cancers acquire inactivating mutations in p53 that are associated with resistance to chemotherapy, Apo2L/TRAIL and its apoptosis-signaling receptors may provide an alternative pathway to switching on apoptosis in tumors. Preclinical studies demonstrate promising apoptosis-based anti-tumor activity of Apo2L/TRAIL and a strong cooperation between this biologic agent and chemotherapy. Apo2L/TRAIL is jointly being prepared by Genentech and Amgen for human clinical trials.

Tasidotin
Tasidotin is a novel tubulin-interactive agent that is currently being studied in Phase II metastatic melanoma, non-small cell lung cancer and prostate cancer clinical trials.

The agent is a synthetic dolastatin analog and has a unique mechanism of action that potentially differs from that of microtubule-stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and other dolastatins). It has been chemically modified to provide improved pharmacological properties and is orally bioavailable with a potentially enhanced therapeutic window over earlier-generation dolastatins.

Results of a Phase I study recently presented by clinical investigators at the 2004 American Society of Clinical Oncology annual meeting showed that tasidotin appears to be biologically active and well-tolerated in patients with advanced refractory solid tumors. Preliminary safety data from the Phase II metastatic melanoma trial were also presented at ASCO and showed that tasidotin appears to be safe, tolerable and convenient for patients as administered in that trial.

DENSPM
We accelerated our activity in small molecule approaches to oncology with a phase 1-2 trial of DENSPM, a compound that has demonstrated early activity in a variety of solid tumors. We will investigate the potential of this compound in liver cancer, an indication that has Orphan Drug status.