All about Targeted Drugs for Breast Cancer !

Breast cancer is one of the common malignant tumors of females, with incidence rising year by year and the tendency of patients getting younger. As an effective therapeutic regimen, breast cancer targeted therapy has strong specificity, small toxic and side effects, and basically no damage to normal tissues. With the deepening of the pharmacological and molecular biological research, the research and application of the relevant targeted drugs have achieved breakthroughs, and the R&D of drugs for new therapeutic targets has become a hotspot that attracts people’s attention.

Targeted therapies design corresponding therapeutics for carcinogenic sites that have been made clear at the cell molecular level, which will accurately bind to the carcinogenic sites and function after entering bodies. Therefore, what is the most critical in treatment with targeted drugs is to choose the appropriate targets. Currently, the proved targets of breast cancer mainly include human epidermal growth factor receptor 2 (HER2), mammalian target of rapamycin (mTOR) signaling pathway, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), poly (ADP-ribose) polymerase (PARP), and cyclin-dependent kinases 4/6 (CDK4/6).

As world’s first humanized monoclonal antibody against HER2, trastuzumab (trade name: Herceptin) has been marketed for many years in China and entered the medical insurance coverage of China. According to data, one year of adjuvant therapy with Herceptin can effectively reduce the risk of recurrence. It is the "life-saving drug" for patients with HER2-overexpressing metastatic breast cancer. Pertuzumab (trade name: Perjeta) is another humanized monoclonal antibody against HER2 target, which mainly binds to HER2 receptor extracellular domain II, is effective for high (low) HER2-expressing breast cancer, and can double block different targets, thus to achieve better therapeutic effect. Marketed in June 2012 in the U.S., Perjeta has become a full-course drug of choice to patients with HER2-positive breast cancer. Lately there has been news from the 21st Annual Meeting of the CSCO that Roche has filed relevant application to the Center for Drug Evaluation, CFDA in August, meaning that Perjeta is hopefully to be marketed soon in China. As a quinazoline derivative, lapatinib is an oral, new small molecule tyrosine kinase inhibitor that can act on both EGFR and HER2; it is used in combination with capecitabine to treat patients with ErbB2 (i.e., HER2 gene)-overexpressing advanced or metastatic breast cancer who have received taxane, anthracycline and trastuzumab treatment. Other drugs acting on HER2 target also include T-DM1 and neratinib, wherein, T-DM1 is a new HER2 targeted drug combining trastuzumab, tubulin inhibitor maitansine and DM1, and neratinib is an irreversible pan-ErbB2 receptor tyrosine kinase inhibitor against HER2 and HER1.

Phosphatidylinositol-3-kinase / protein kinase B / mammalian target of rapamycin (PI3K / Akt / mTOR) is an important signaling pathway in cells, and plays an important role in tumor cell proliferation, angiogenesis and metastasis, and radiotherapy and chemotherapy antagonism. According to research, PI3K / Akt / mTOR signaling pathway plays a critical role in breast cancer occurrence and development. Currently, breast cancer drugs targeting PI3K / Akt / mTOR signaling pathway include GDC-0941, BEZ235, Buparlisib, Alpelisib, temsirolimus, and MLN0128, etc.

VEGF is a key factor of angiogenesis, and tumor angiogenesis is an important factor resulting in tumor growth, metastasis and infiltration, therefore, treatment against VEGF has become a key in anti-tumor angiogenesis treatment, and vascular targeted therapy has become one of the therapeutic strategies for breast cancer. As world’s first recombinant DNA humanized monoclonal antibody against VEGF-A, bevacizumab (Avastin) can selectively bind to VEGF to block its biological activity, affect angiogenesis, and thus inhibit tumor growth. Sorafenib is a multitargeted anti-angiogenesis oral drug that can inhibit many tyrosine kinase receptors including VEGFR, thereby inhibiting angiogenesis and tumor growth. In addition, there is also the fully humanized monoclonal antibody ramucirumab that targets VEGF2 and multitargeted tyrosine kinase inhibitor sunitinib.

EGFR is a transmembrane receptor with tyrosine kinase activity; it plays an important role in the development, maturity and degeneration of normal breast, and is also associated with tumor cell proliferation, metastasis, invasion, angiogenesis, and apoptosis inhibition. EGFR-targeting drugs include gefitinib, cetuximab, and erlotinib.

CDK4/6 is a kind of serine/threonine kinase that binds to cyclin D to regulate cells to transit from G1 to S phase. The losing control of cell cycle is an important factor in cancer occurrence and development, and CDK4/6 is a key factor in such losing control. Palbociclib Capsules of Pfizer was approved for marketing by the U.S. FDA on February 3, 2015, which is used in combination with letrozole for women with estrogen receptor-positive (ER+) and HER2- advanced breast cancer, being the first CDK4/6 inhibitor approved. The oral cancer targeted drug: ribociclib (formerly known as LEE011) developed by Novartis was approved by FDA on March 13, 2017, which can be used in combination with aromatase inhibitor to serve as the first-line therapy for post-menopausal women with HR+/HER2- advanced metastatic breast cancer, being the second CDK4/6 inhibitor marketed in the world.

There have been 16 targeted drugs approved for breast cancer, however, there are restrictions on the use of those drugs. Targeted drugs can truly achieve "precision targeted therapy" of breast cancer only after the gene mutational sites are made clear through gene detection.

References

 [1] All What You Want to Know about Breast Cancer Targeted Drugs! (By September 2018)

 [2] Zhong Weilan, Lu Meiyu, Si Chunfeng et al. Progress of Research on Targeted Therapy for Breast Cancer [J]. Journal of Modern Oncology, 2018(4):622-626.

About the author: Xiaonisha, a practitioner in food science and technology, graduated from School of Food Science and Engineering in South China University of Technology as a Master of Food Science, and now works at a large drug R&D company in China, engaging in R&D of nutritional food.

-----------------------------------------------------------------------
Editor's Note:

To apply for becoming a contributor of En-CPhI.cn,

welcome to send your CV and sample works to us,

Email: Julia.Zhang@ubmsinoexpo.com.