1. Field of the Invention
This invention relates to methods for predicting the response to cancer therapy in an individual.
2. Background of the Invention
Cellular growth and differentiation processes involve growth factors that exert their actions through specific receptors expressed in the surfaces of responsive cells. Ligands binding to surface receptors, such as those that carry an intrinsic tyrosine kinase activity, trigger a cascade of events that eventually lead to cellular proliferation and differentiation (Carpenter et al., Biochem., 48: 193-216, 1979; Sachs et al., Cancer Res., 47: 1981-1986, 1987). Receptor tyrosine kinases can be classified into several groups on the basis of sequence similarity and distinct features. One of these groups includes the epidermal growth factor receptor family, which included erbB-1 (EGFR or HER-1) (Carpenter et al., Biochem., 48: 193-216, 1979); erbB-2 (HER-2/neu) (Semba et al., Proc. Natl. Acad. Sci., 82: 6497-6501, 1985; Coussens et al., Science, 230: 1130-1139, 1985, Bargmann et al., Cell, Vol. 45, 649-657, 1986); erbB-3 (HER-3) (Kraus et al., Proc. Natl. Acad. Sci., 86: 9193-9197, 1989; Carraway et al., R. A. J. Biol. Chem., 269: 14303-14306, 1994), and erbB-4 (HER-4) (Plowman et al., Nature, 366: 473-475, 1993; Tzahar et al., Biol. Chem., 269: 25226-25233, 1994).
As an example of a ligand that can bind to surface receptors, NDF (neu differentiation factor)/Heregulin is a receptor tyrosine kinase ligand that can stimulate the tyrosine phosphorylation of erbB-2 through heterodimerization with its receptors erbB-3 or erbB-4 (Peles, et al., Cell, 69:205-216, 1992, Peles, et al., EMBO J. March;12(3):961-71, 1993; Holmes et al, Science, 256:1205-1210, 1992. Tzahar et al., Biol. Chem., 269: 25226-25233, 1994; Plowman et al., Nature, 366: 473-475, 1993; Pinkas-Kramarski et al., Proc. Natl. Acad. Sci., 91:9387-9391, 1994; Pinkas-Kramarski et al., The Journal of Biological Chemistry, Vol. 271, No. 32: 19029-19032, 1996; Pinkas-Kramarski et al., Oncogene, 16, 1249-1258, 1998.). Depending on the cell line studied, NDF/Heregulin can either elicit a growth arrest and differentiation phenotype, resulting in morphological changes, induction of lipids, and expression of intracellular adhesion molecule-1, or induce a mitogenic response (Holmes et al., Science, 256:1205-1210, 1992; Peles et al., Cell, 69:205-216, 1992; Bacus et al., Cancer Res. 53:5251-5261, 1993).
Activation of erbB receptor heterodimers is coupled to and stimulates downstream MAPK-Erk1/2 and PI3K-AKT growth and survival pathways whose deregulation in cancer has been linked to disease progression and refractoriness to therapy (Olayioye, M. A., et al., Mol. Cell. Biol. 18, 5042-5051 (1998), Fukazawa, T., et al., J. Biol. Chem. 271, 14554-14559 (1996), Hackel, P. O., et al., Curr. Opin. Cell Biol. 11, 184-189 (1999); Tzahar, E., et al., Mol. Cell. Biol. 16, 5276-5287 (1996); Lange, C. A., et al., J. Biol. Chem. 273, 31308-31316 (1998). For example, HER-3 is a major docking site for phoshoinositide-3-kinase (PI3K). In addition, NDF/Heregulin stimulation causes activation of the PI3K pathway and phosphorylation of AKT (Altiok et al., J. Biol. Chem., 274, 32274-32278, 1999; Liu et al., Res. Comm., 261, 897-903, 1999; Xing et al., Nature Med., 6, 189-195, 2000). These observations implicate PI3K/AKT in the signaling cascade that results from HER-3 heterodimerization with overexpressed HER-2/neu receptors in breast cancer cells; activation of PI3K/AKT promote cell survival and enhanced tumor aggressiveness (Shak, Semin. Oncol., Suppl 12:71-77, 1999; Huang et al., Clinical Cancer Res., Vol. 7: 2166-2174, 2000). In addition, AKT2 was reported to be activated and overexpressed in HER-2/neu-overexpressing breast cancers (Bacus et al., Oncogene, 21: 3532-3540, 2002).
Most tumors of epithelial origin express multiple erbB (HER) receptors and co-express one or more EGF-related ligands suggesting that autocrine receptor activation plays a role in tumor cell proliferation. Because these ligands activate different erbB/HER receptors, it is possible that multiple erbB receptor combinations might be active in a tumor, a characteristic that could influence its response to an erbB-targeted therapeutic. For example, erbB-2/HER-2 is overexpressed in 20 to 30% of all breast cancers, and its overexpression is associated with poor prognosis, suggesting that it could be used as a target for anti-tumor agents (Slamon et al., Science, 235: 177-182, 1987; Tagliabue et al., Int. J. Cancer, 47: 933-937, 1991; Hudziak et al., Mol. Cell. Biol., 9: 1165-1172, 1989). Studies have shown that in erbB-2 overexpressing breast cancer cells, treatment with antibodies specific to HER-2/erbB-2 in combination with chemotherapeutic agents (e.g., cisplatin, doxoubicin, taxol) elicits a higher cytotoxic response than treatment with chemotherapy alone (Hancock et al., Cancer Res., 51: 4575-4580, 1991; Arteaga et al., Cancer, 54:3758-3765, 1994; Pietras et al., Oncogene, 9: 1829-1838, 1994). One possible mechanism by which HER-2/erbB-2 antibodies might enhance cytotoxicity to chemotherapeutic agents is through the modulation of the HER-2/erbB-2 protein expression, (Bacus et al., Cell Growth & Diff., 3: 401-411, 1992, Bacus et al., Cancer Res. 53:5251-5261, 1993; Stancovski et al., Proc Natl Acad Sci USA 88: 8691-8695, 1991; Klapper et al., Oncogene 14, 2099-2109, 1997, and Klapper et al., Cancer Res., 60: 3384-3388, 2000), or by interfering with DNA repair (Arteaga et al., Cancer, 54:3758-3765, 1994, and Arteaga et al., J Clinical Oncology, Vol. 19, No 18s, 32s-40s, 2001; Pietras et al., Oncogene, 9: 1829-1838, 1994).
Because of the effect of anti-HER-2/erbB-2 antibodies on cellular growth, a number of approaches have been used to therapeutically target HER-2/erbB-2 or EGFR overexpressing cancers. For clinical use, one approach is to interfere with the kinase activity of the receptor by using inhibitors that block the nucleotide binding site of HER-2/neu or EGFR (Bruns, et al., Cancer Research, 60,2926-2935, (2000); Christensen, et al, Clinical Cancer Research, Vol. 7, 4230-4238, 2001, Erlichman, et al., Cancer Research 61, 739-748, 2001, Fujimura, et al., Clinical Cancer Research, Vol. 8, 2448-2454, 2002; Herbst, et al., Journal of Clincal Oncology, Vol. 20, No. 18, 3815-3825, 2002; Hidalgo, et al, J. Clinical Oncology, Vol 19, No 13: pp 3267-3279, 2001; Moasser, et al., Cancer Res., 61: 7184-7188, 2001; Normanno, et al., Ann. of Oncol., 13: 65-72, 2002). A second approach is using ansamycins to influence the stability of HER2/neu receptors (Munster, et al., Cancer Research 62, 3132-3137, 2002; Basso et al, Oncogene, 21: 1159-1166, 2002). Another approach is the use of antibodies directed to various erbB receptors specifically EGFR or HER-2/neu (Alaoui-Jamali, et al Biochem. Cell. Biol., 75:315-325, 1997; Albanell, et al., J. National Cancer Institute, Vol 93, No. 24, 1830-31, 2001; Baselga, et al., Pharmacol Ther 64: 127-154, 1994 and Baselga, et al., Annuals of Oncology 13: 8-9, 2002; Mendelsohn, Seminars in Cancer Biology, Vol. 1, pp. 339-344, 1990). A number of monoclonal antibodies and small molecule, tyrosine kinase inhibitors targeting EGFR or erbB-2 have been developed. For example, HERCEPTIN® is approved for treating the 25% of women whose breast cancers overexpress erbB-2 protein or demonstrate erbB-2 gene amplification (Cobleigh, M. A., et al., J. Clin. Oncol. 17, 2639-2648 (1999)). Analysis of various antibodies to HER-2/neu has led to the identification of the murine monoclonal, 4D5. This antibody recognizes an extracellular epitope (amino acids 529 to 627) in the cysteine-rich II domain that resides very close to the transmembrane region. Treatment of breast cancer cells with 4D5 partially blocks NDF/heregulin activation of HER-2-HER-3 complexes, as measured by receptor phosphorylation assays. To allow for chronic human administration, murine 4D5 was humanized to generate HERCEPTIN® (trastuzumab) (Sliwkowski et al, Sem. in Oncol., 26:60-70, 1999; Ye et al., Oncogene, 18: 731-738, 1999; Carter et al, Proc. Natl. Acad Sci USA 89:4285-4289, 1992; Fujimoto-Ouchi et al, Cancer Chemother Pharmacol, 49: 211-216, 2002; Vogel, et al., Oncology, 61(suppl 2):37-42, 2001; Vogel, et al., Journal of Clinical Oncology, Vol 20, No. 3:719-726, 2002). In addition, several EGFR-targeted therapies are currently under clinical investigation (Mendelsohn, J., & Baselga, J., Oncogene 19, 6550-6565 (2000); Xia, W., et al. Oncogene 21, 6255-6263 (2002)). In particular, a human anti-EGFr monoclonal antibody, designated ABX-EGF (and also referred to herein as ABX-0303, as described in detail in U.S. Pat. No. 6,235,883; the disclosure of which is hereby incorporated by reference), is being developed by Abgenix, Inc. and Immunex Corporation (Yang X et al. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hemato 38(1):17-23 (2001); Yang X-D et al. Eradication of Established Tumors by a Fully Human Monoclonal Antibody to the Epidermal Growth Factor Receptor without Concomitant Chemotherapy. Cancer Research 59(6):1236-1243 (1999)).
Historically, cytotoxic cancer therapies have been developed based on maximum tolerated doses (MTD), treating patients without understanding the tumor profile for likely responders. Hence, patients were often subjected to toxic therapies with limited therapeutic benefit. Recently, elucidating tumor growth and survival pathways has led to the development of tumor-targeted therapies. An example of this approach is Gleevec™, an inhibitor of the c-abl family of tyrosine kinases approved for treating chronic myeloid leukemia and gastrointestinal stromal tumors (Druker, B. J. et al., N. Engl. J. Med. 344, 1031-1037 (2001); Demitri, G. D., et al.; N. Engl. J. Med. 347, 472-480 (2002)).
In contrast, most erbB-receptor targeted therapies primarily exert cytostatic anti-tumor effects, necessitating their chronic administration. Identification of biologically effective doses (BED), the dose or dose range that maximally inhibits the intended target, beyond which dose escalation is likely to add toxicity without benefit, is therefore essential. Moreover, many of these agents will be used in combination with cytotoxic therapies, where added toxicity may not be tolerable, further supporting BED-based dosing. Targeted-therapy implies that populations of likely responders exists, and can be identified.
In view of the severe and deleterious consequences of administering an inappropriate or ineffective therapy to a human cancer patient, there exists a need in the art for predicting the response to cancer therapy in an individual.