Areas of Research

Our pipeline is broad and deep

Cancer results from multiple mutations that cause cells to grow uncontrollably. In recognition of the many steps of carcinogenesis, the Novartis Oncology pipeline encompasses a broad array of therapeutic strategies. Our wide range of multitargeted approaches to cancer therapy reflects our continued commitment to cancer care— from bench to clinic.

Strategies for fighting cancer

Cancer drug development has become a focused strategy as a result of a solid foundation in the basic sciences. Novartis Oncology targets are selected based on extensive research to understand the molecular structure of drug receptors, the specific biochemical characteristics of intracellular proteins, the unique products of aberrant genes, and the cellular process underlying the etiology of cancer. State-of-the-art technology is used to identify the best compounds in order to exploit specific molecular targets accurately and effectively. When a natural compound is not readily found, synthetic molecules that mimic the natural ligands of receptors can be engineered from the understanding of the underlying mechanisms gleaned from previous research.

 

Targeted Kinase Inhibitors

Many protein kinases, including both cellular receptor kinases and intracellular kinases, are key components of signal transduction pathways that control cell proliferation, differentiation, and apoptosis. In many cancers, some signaling pathways are often inappropriately activated by mutation and/or overexpression of certain kinases.

Targeting aberrant pathways through kinase inhibition has proven to be an effective strategy to specifically inhibit the g rowth of tumor cells.

Certain kinases in endothelial cells, such as vascular endothelial growth-factor receptor (VEGFR), play important roles in the stimulation of the growth of new blood vessels (angiogenesis). Tumor angiogenesis is the proliferation of blood vessels that penetrate into cancerous growths, supplying nutrients and oxygen to assist tumor growth. By blocking signaling pathways involved in angiogenesis, drugs may potentially halt tumor growth and spread (metastasis).

 

Targeting Tumor Growth

• Nilotinib (AMN107): Bcr-Abl inhibitor
• Midostaurin (PKC412): Multiple kinase-signal-transduction inhibitor

 

Targeting Both Tumor and Angiogenesis

• BEZ235: PI3K inhibitor
• RAD001 (everolimus): mTOR inhibitor
• TKI258: Multitargeted receptor tyrosine kinase inhibitor (TKI)
• RAF265: Raf and VEGFR inhibitors
• AEE788: VEGFR, EGFR, and HER-2 inhibitors

 

Deacetylase (DAC) Inhibitors

Deacetylases (DACs) are enzymes that can regulate transcription and other cellular processes by the removal of acetyl groups from target proteins. DACs are novel intracellular targets for therapeutic agents.

DAC inhibition is an important approach in oncology because it is inherently multitargeted. The ability to interfere with multiple targets with a single agent is a desirable trait when treating cancers with complex biology.

The first target traditionally associated with DACs is the histone—the core proteins around which DNA is wrapped, which is why DACs are sometimes referred to as histone deacetylases (HDACs). DAC activity is associated with DNA modifications that lead to increased growth and proliferation of cancer cells. Targeting the histone is part of the rapidly evolving field of epigenetics. Epigenetic changes may be as important as genetic mutations in driving several types of cancers.

The second major target for DACs is nonhistone proteins, which have been shown to modulate cancer-cell growth and survival pathways. The nonhistone proteins may be more important targets than histones in the treatment of some cancers.

DAC inhibitors can be classified into:

• Specific DAC inhibitors that target Class I DACs (with histones as the primary substrate)
• Pan-DAC inhibitors that target both Class I and Class II DACs (with histone and nonhistone substrates)

The Novartis Oncology pipeline includes the pan-DAC inhibitor LBH589.

 

Novel Cytotoxics

Chemotherapy drugs have been used effectively in cancer treatment since the early 1950s to destroy rapidly dividing cancer cells. However, some normal cells also grow and divide quickly, and can be affected by chemotherapy. Damage to these normal cells causes side effects. Despite the associated toxicities, chemotherapeutic agents remain the backbone of combination regimens that now include targeted agents. Novel strategies to optimize chemotherapy therefore have important roles to play in cancer therapy.

As a leader in the field of oncology, Novartis Oncology is developing the next generation of cytotoxic agents through improved genetic and proteomic understanding of cancers, which will offer new and improved cytotoxic agents to complement targeted-therapy approaches in discovery.

Novel cytotoxics in the Novartis Oncology pipeline include

• Patupilone (EPO906): Microtubule stabilizer
• Gimatecan (LBQ707): Topoisomerase I inhibitor

 

Monoclonal Antibodies

Monoclonal antibodies (mAbs) exhibit a high degree of target specificity that may result in efficient attack of cancer cells, while in some cases sparing normal cells the toxicity often associated with chemotherapy. As such, they offer several advantages over many of the current regimens for cancer therapy.

mAbs can fight cancer through multiple mechanisms of action. They can bind to receptors on the tumor-cell surface to block signal transduction that is crucial for tumor growth and proliferation. They can recruit the body's own immune system to destroy cancer cells by binding to specific receptors on cancer cells, a process called antibody-dependent cell cytotoxicity (ADCC). They can also induce tumor-cell death by stimulating the apoptosis pathway.

The Novartis Oncology pipeline includes 2 mAbs: the antagonistic anti-CD40 HCD122 and the agonistic anti-DR5 LBY135.

 

Multiligand Somatostatin Analogues

The peptide hormone somatostatin, expressed in many tissues, is a key regulator of other hormones that may stimulate the growth and proliferation of some tumor types. Somatostatin inhibition is a strategy that has been explored in other therapeutic categories, such as Cushing's disease and acromegaly. Currently, this strategy is beginning to be investigated in oncology.

The Novartis Oncology pipeline includes the multiligand somatostatin analogue pasireotide (SOM230).