Drug Targets for Breast Cancer

Drug Targets for Breast Cancer

Drug targets for breast cancer: pharmacology information

Drug targets for breast cancer: bioreagents

Drug Targets HER2 for Breast Cancer with Approved Drugs

Drug targets Cancer drugs Company
HER2 Trastuzumab Roche
HER2 Pertuzumab Roche
HER2 Lapatinib GSK

Data from transfection studies and transgenic mice suggest a role for HER2 in the pathogenesis of breast cancer, which agrees with prognostic studies. Immunostaining of primary tumors revealed that when a tumor is positive, it usually shows a very homogeneous staining of all tumor cells including the preinvasive and metastatic components. In fact, a number of groups have reported a higher incidence of HER2 overexpression in ductal carcinoma in situ versus infiltrating ductal carcinoma. Hudziak showed that colony formation of NIH-3T3 cells transformed by HER2 overexpression could be inhibited by an anti-HER2 antibody. Drebin reported that an anti-neu monoclonal antibody generated against mutated rat neu protein inhibited growth of NIH. The extracellular domain (ECD) of the HER2 protein binds extracellular ligands and transduces a signal to the cell via tyrosine kinase activity of its intracellular domain. Substantial effort in many laboratories studying EGF and other growth factor receptors has been made towards uncovering the molecules that constitute the pathway carrying the mitogenic signal. Potential members of the signalling pathway for growth factor receptors include phospholipase C, the oncogene derived protein raf-1, GAP, and calpactin-like molecules. (Ref: Lupu R, Lippman M E. The role of erbB2 signal transduction pathways in human breast cancer[J]. Breast cancer research and treatment, 1993, 27(1): 83-93.)

Drug Targets CDK4/CDK6 for Breast Cancer with Approved Drugs

Drug targets Cancer drugs Company
CDK4 Palbociclib Pfizer
CDK6 Palbociclib Pfizer

Mouse models of human breast cancer confirm that activation of the cyclin D1-CDK4–6 axis contributes towards a tumourigenic phenotype and is critical for the initiation and maintenance of tumourigenesis in HER2-positive breast cancer, whereas neither CDK 2 nor CDK4/6 knockout adversely affects viability or normal mammary development. CDK4/6-cyclin D1 activity is deregulated by multiple mechanisms in breast cancer and such deregulation is common. A recent cancer genome dataset-based study of 482 patients with invasive breast cancer reported that 27.4% had genetic deregulation of the cyclin D1/ CDK4/6/p16Ink4a axis either in the form of a single gene alteration in the axis or multiple gene alterations in combination. Cyclin D1 overexpression occurs in approximately half of breast cancer cell lines. The cyclin D1 gene, CCND1, is, however, amplified in only 20% of breast cancers. The disparity between gene amplification and protein overexpression may be attributed in part to mutations in the cyclin D1 turnover pathway. (Ref: Dukelow T, et al. CDK4/6 inhibitors in breast cancer[J]. Anti-cancer drugs, 2015, 26(8): 797-806.)

Drug Targets mTOR for Breast Cancer with Approved Drugs

Drug targets Cancer drugs Company
mTOR Everolimus Novartis

The PI3K (phosphoinositide-3-kinase)/Akt (protein kinase B)/mTOR (mechanistic target of rapamycin) pathway responds to nutrient availability and growth factor tyrosine kinases. It plays a significant role in stimulating protein synthesis, angiogenesis and tumor proliferation, and inhibiting apoptosis. The pathway starts with the PI3K unit, which comprises two subunits, the regulatory (p85) and the catalytic (p110) subunit; each has different isoforms and is encoded by its corresponding genes. The regulatory subunit is encoded by PIK3R1, PIK3R2, PIK3R3 and the p110α, p110β, and p110δ subunits are encoded by PIK3CA, PIK3CB and PIK3CD. PI3K leads to the phosphorylation of Akt, a serine/threonine kinase, which activates the mechanistic (or mammalian) target of rapamycin (mTOR) by inhibiting the tuberous sclerosis complex proteins 1/2 (TSC1/2). mTOR is a serine/threonine protein kinase that consists of complexes mTORC1 (mTOR Complex 1) and mTORC2 (mTOR Complex 2). mTORC1 is the main target of rapamycin analogs, while more recent data suggest that mTORC2 is also inhibited with sufficient dosing and exposure.The mTOR inhibitor, Everolimus is approved for the treatment of advanced hormone receptor-positive breast cancer and is currently being evaluated in other breast cancer subtypes. (Ref: Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520-529.)

Drug Targets VEGF-A for Breast Cancer with Approved Drugs

Drug targets Cancer drugs Company
VEGF-A Bevacizumab Roche

A recent study reported that VEGF protein is expressed in human breast cancer, with both VEGF-B (preferentially expressed in endothelial cells) and VEGF-C (associated with development of lymphatic vessels) also being expressed at lower levels. In a study that evaluated 46 breast biopsies from ductal carcinoma in situ lesions, significant association was found between VEGF mRNA expression and the degree of angiogenesis. The same group of investigators found strong tumor cell expression of VEGF in half of the ductal breast carcinomas in situ and strong or moderate VEGF expression in most of the invasive carcinomas examined. Strong intratumoral endothelial cell expression of VEGF receptors was also observed. Therefore, VEGF could be an important marker of angiogenic activity for prognostic purposes as well as for targeting inhibition of angiogenesis as a novel therapeutic strategy against breast cancer. (Ref: Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer[J]. The oncologist, 2000, 5(Supplement 1): 37-44.)

Drug targets for Breast cancer: Related Information