In 2004, approximately 500,000 people are expected to die of cancer in the US alone. Cancer is the second leading cause of death in the US and expected to surpass cardiovascular disease as the number one killer.
 

The Oncology group at the Novartis Institutes for BioMedical Research (NIBR) encompasses most therapeutic modes, including anti-angiogenesis agents, neocytotoxics, and drugs that target cellular transformation. The kinase franchise in particular has matured into a very fruitful operation,

responsible for innovative drugs such as Glivec®/Gleevec® (see "Marketed products".)  Over the past few years, exciting drug candidates have been produced, including Raf kinase inhibitors, multi-targeted kinase drugs, and histone deacetylase (HDAC) inhibitors, compounds that act via a novel therapeutic mechanism called epigenetic modulation.
 

At NIBR we will concentrate our forces on three fronts: 1) targeted therapies that build on the success of Glivec; 2) neocytotoxics that attack essential cellular functions with molecular precision; and 3) drug combinations. New target classes will be scrutinized in quantitative validation assays. We will also explore antibody therapeutics, a step that more than doubles the list of target candidates and utilizes our current expertise and reagents in new ways.

The Oncology team - headed by William Sellers - is deployed equally between Basel, Switzerland and Cambridge, USA.

Traxler P, Allegrini PR, Brandt R, Brueggen J, Cozens R, Fabbro D, Grosios K, Lane HA, McSheehy P, Mestan J, Meyer T, Tang C, Wartmann M, Wood J, Caravatti G. AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2004 Jul 15; 64(14):4931-41.

Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A, Cornell-Kennon S, Lee J, Wang B, Wang J, Memmert K, Naegeli HU, Petersen F, Eck MJ, Bair KW, Wood AW, Livingston DM. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell. 2004 Jul; 6(1):33-43.

Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro.Cancer Res. 2004 Apr 1; 64(7):2333-7.

Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG, Liebetanz J, Martiny-Baron G, Ruetz S, Hofmann F. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell. 2004 Mar; 5(3):231-9.

Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, Garcia-Echeverria C, Pearson MA, Hofmann F, Anderson KC, Kung AL. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004 Mar; 5(3):221-30.

Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov. 2003 Dec; 2(12):999-1017. Review. No abstract available.

Ellis MJ, Coop A, Singh B, Tao Y, Llombart-Cussac A, Janicke F, Mauriac L, Quebe-Fehling E, Chaudri-Ross HA, Evans DB, Miller WR. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res. 2003 Oct 1; 63(19):6523-31.

Freedman SJ, Sun ZY, Kung AL, France DS, Wagner G, Eck MJ. Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Nat Struct Biol. 2003 Jul; 10(7):504-12.

Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM, Curley DP, Duclos N, Rowan R, Kutok JL, Lee BH, Williams IR, Coutre SE, Stone RM, DeAngelo DJ, Marynen P, Manley PW, Meyer T, Fabbro D, Neuberg D, Weisberg E, Griffin JD, Gilliland DG. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease.Cancer Cell. 2003 May; 3(5):459-69.

Connolly DC, Bao R, Nikitin AY, Stephens KC, Poole TW, Hua X, Harris SS, Vanderhyden BC, Hamilton TC. Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer. Cancer Res. 2003 Mar 15; 63(6):1389-97.

Selvakumaran M, Pisarcik DA, Bao R, Yeung AT, Hamilton TC. Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res. 2003 Mar 15; 63(6):1311-6.

Kurokawa H, Katsube K, Podyma KA, Ikuta M, Iseki H, Nakajima M, Akashi T, Omura K, Takagi M, Yanagishita M. Heparanase and tumor invasion patterns in human oral squamous cell carcinoma xenografts.Cancer Sci. 2003 Mar; 94(3):277-85.

Warmuth M, Simon N, Mitina O, Mathes R, Fabbro D, Manley PW, Buchdunger E, Forster K, Moarefi I, Hallek M. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood. 2003 Jan 15; 101(2):664-72. Epub 2002 Sep 05.

Glivec®/Gleevec® (imatinib)
This is Novartis' breakthrough drug for Chronic Myeloid Leukemia (CML). It is a signal transduction inhibitor that works by targeting the primary cause of the disease, a protein product of an abnormal chromosome called the Philadelphia chromosome. Glivec has also dramatically impacted the diagnosis and management of Gastro-intestinal Stromal Tumors (GIST). Glivec is the first medicine in the world that has been tailor-made for a specific pathogenetic gene product. For many, this therapeutic alternative known as "targeted therapy" represents the future of anti-cancer therapy and is poised to change the way cancer drugs are developed and manufactured.

Femara® (letrozole tablets)
This drug is indicated for the treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. This drug prolongs survival and reduces cancer recurrence compared to other hormonal treatments in large, controlled studies.

Zometa® (zoledronic acid)
Zometa is a treatment for hypercalcemia of malignancy and for the treatment of bone metastases across a broad range of tumor types. It reduces the ability of tumors to destroy and grow within the bone.

Sandostatin® (octreotide/IM injection)
This product is the most prescribed and most studied medical therapy in the treatment of acromegaly and symptoms of gastro-entero-pancreatic neuroendocrine tumours.

PTK787 is positioned to be the first oral targeted angiogenesis inhibitor and is a co-development, co-marketing project with Schering AG. PTK787 attacks the fundamental need of tumors for a blood supply, a recently validated new mechanism of action for cancer therapy. A large Phase III study is underway for PTK787 in first and second line treatment of colorectal cancer.

ICL670, an oral, once daily iron chelating agent, could bring a major improvement to the quality of life of patients with iron overload in transfusion-dependent amenias.

AEE788 is a multi-targeted kinase inhibitor that combines 3 activities known to be required for tumor growth.  It is a combination therapy wrapped into a single molecule and may find use in lung, breast, and other tumor types.  A Phase I study is underway.