As with all of our discovery research at Millennium, our work in the area of cancer is focused on understanding the key molecular pathways that underlie the various forms of disease, and identifying therapeutically important differences that may exist between people. The depth and breadth of our programs in cancer can be illustrated by highlighting our efforts in four key areas: proteasome inhibition, kinases and personalized medicine.

Proteasome inhibition is a new strategy in cancer treatment The proteasome is an enzyme complex within the cell responsible for breaking down proteins that have been marked for removal by the attachment of a tag called ubiquitin. The ubiquitin-proteasome pathway plays an essential role in regulating the concentration of specific proteins inside the cell, thereby maintaining 'homeostasis', the natural tendency of the cell to remain stable. Inhibition of the proteasome prevents this targeted proteolysis which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that proteasome inhibition is cytotoxic to a variety of cancer cell types in vitro, and causes a delay in tumor growth in vivo in non-clinical tumor models. For more information about VELCADE® (bortezomib) for Injection, click here.

Kinases play an important role in the control of many cellular functions, which is why they are a major focus of our research in disease biology. The key reaction catalyzed by kinases is the addition of phosphate groups at specific sites on selected proteins. Each of the proteins modified by a kinase undergoes some change in behavior as a result of this phosphorylation, causing it to modify additional proteins. In this way, a single initial event – the event which activated the kinase – can be propagated via cascading pathways into major changes in the overall behavior of the cell. Specific events that activate kinases are therefore of interest to cancer researchers. One important event is the binding of a growth factor to a receptor that has an intracellular tyrosine kinase activity. This activates the kinase (known as a receptor tyrosine kinase, or RTK), triggering pathways that ultimately result in growth and division of the cell. In certain forms of cancer it appears that a key underlying cause of the malignant growth is a hyperactive RTK, which leads to uncontrolled cell proliferation. In such cases, an inhibitor of the RTK may have a powerful therapeutic effect. Millennium is actively developing inhibitors of an RTK known as the FLT-3 kinase which has been implicated in acute myeloid leukemia and other forms of cancer.

In addition to RTKs, there are many other types of kinases that play important roles in signaling pathways within the cell that lead to cell growth, and Millennium is exploring many different members of the kinase family as potential targets for novel, selective anti-cancer drugs that could represent real therapeutic breakthroughs.

Therapeutic antibodies have enormous potential for the treatment of cancer. Antibodies have the ability to seek out and bind to their target antigens with high specificity and affinity. If those antigens are proteins found only or predominantly on the surfaces of cancer cells, antibodies should be capable of selectively recognizing and targeting these cells with virtually no recognition of normal cells. In some cases, the antibody by itself may be all that is needed to achieve the desired therapeutic effect. In other cases, the best results may be obtained by attaching a lethal payload to the antibody, such as radioactivity or a chemotherapeutic agent. Millennium is exploring all of these potential avenues, but with an emphasis on using monoclonal antibodies as vehicles to target lethal payloads to tumor cells. A crucial goal is therefore to find an appropriate targeting monoclonal antibody vehicle (T-MAV) for each product of this type that we seek to develop.

The key first step in pursuing this goal is to identify appropriate cell-surface proteins that are present only or predominantly on tumor cells. To achieve this, we have deployed our leading technology platform to survey the expression patterns of large numbers of genes in a comprehensive range of tumor samples, collected through collaborations with major academic oncology centers. Using advanced informatics analyses to compare these expression patterns with those in corresponding normal tissues, we have been able to identify a significant number of cell-surface proteins whose expression correlates with the incidence and progression of different forms of cancer.

Once we have identified candidate cell-surface proteins, we make use of the full modern repertoire of antibody-generating technologies to select antibodies with appropriate properties for further development as drug candidates. In suitable cases, we then draw on our considerable expertise in conjugation technology to attach lethal payloads to antibodies we have selected for our T-MAV program. Overall, we believe that the capabilities we have assembled for every stage of the process — from identification of targets to the preparation of T-MAV conjugates — will allow us to efficiently develop antibody-based products that will have significant impact on the treatment of cancer.

Personalized medicine is a key theme in the approach we take at Millennium to developing breakthrough treatments for important diseases. In the cancer arena, this means conducting detailed studies of gene expression patterns, molecular pathways and genetic differences so that we will be able to identify the appropriate target populations for new drugs that we introduce. These activities include:

The goal of all of this work is to identify appropriate “biomarkers” for use in conjunction with drugs we develop: DNA variants, RNAs or proteins whose presence or abundance can identify the patient groups most likely to respond well to these drugs. We believe these biomarkers will enable us in the future to provide each group with novel treatments that have high efficacy and low toxicity. Such therapies would truly be breakthrough treatments for cancer.