In 1977, Andrzej “Andrew” V. Schally won Nobel Prize in medicine for his research into peptide hormone production in the brain. He described the neurohormone GnRH and other releasing hormones (RH). As initially unexpected application, agonists and antagonists of these hormones have become investigational anti-cancer agents [1-3]. As further developments, Schally and coworkers described targeting gastrin releasing peptide receptors. Gastrin-releasing peptide (GRP) is involved in cancer growth and GRP receptors are expressed in a variety of cancer cells and have limited distribution in normal human tissue. Thus inhibition of GRP receptors represents an attractive target for pharmacological treatment of certain human malignancies [4]. Also, MZ-5-156, an antagonist of growth hormone-releasing hormone (GHRH), decreased cell proliferation and activated AMPK and inhibited Akt, the mammalian target of rapamycin (mTOR) and its downstream target eIF4E which controls protein synthesis and cell growth [5]. GHRH antagonists also caused cell cycle arrest and apoptosis in human colon cancer cells [6, 7].

Yet, this is only one of hundreds examples for new therapeutic targets and new types of drugs that have been developed recently in cellular and animal models. Searche for new targets has continued with many promising lead compounds identified [8-38].

Among promising targets are cancer stem cells [39-42], microRNAs [43-50], the MEK/ERK pathway [51-64] and especially its upstream activator BRAF [61, 65-67] and the NF-kB pathway [68], Myc and HIF-1 [69-72], The CtBP transcriptional corepressors [73], Polycomb group (PcG) proteins [74], autophagy [75-77], translation [78], the proteasome [35], HSP70 [79, 80], Hsp90 [81-84], the AMPK-FoxO3A axis [85], STAT3 and MEK/ERK/BCL-2 signaling [86], the Hh signal transducer Smoothened [87], ErbBs receptor tyrosine kinases [88], and anti-apoptotic members of the Bcl-2 family, Bcl-2, Bcl-X(L) and Mcl-1 [89]. Stromal and endothelial cells are also targets [90, 91]. There are also new targets for anti-angiogenic therapy [71, 75, 78, 92-94]. Also, epithelial mesenchymal transition (EMT) is a critical mechanism for the acquisition of malignant phenotypes by epithelial cells [95]. In colorectal cancer, such cells are histologically represented by tumor buds defined as single cells or small clusters of de-differentiated tumor cells at the invasive front. These buds are also considered as targets for novel cancer therapy [96, 97]. Recently, leukocytes in the ovarian cancer microenvironment such as regulatory T cells and immature pro-angiogenic myeloid cells have been demonstrated to play a fundamental role in tumor progression and have been suggested as potential target [98]. Cdk4/6 is an attractive target for cancer therapy. Thus, a 2-aminothiazole-derived Cdk4/6 selective inhibitor, named Compound A potently inhibits Cdk4 and Cdk6 with high selectivity [99]. Among 82 human cell line examined, leukemia and lymphoma cell lines tended to be more sensitive to Compound A. In a nude rat xenograft model, Compound A inhibited cell proliferation in xenograft tumors at a plasma concentration of 510 nM. Compound A only moderately inhibited cell cycle progression of normal crypt cells in small intestine even at 5 times higher plasma concentration and did not cause immunosuppression even at 17 times higher concentration [99].

Targeting the androgen receptor also has also shown significant progress [100-103]. An interesting example is targeting androgen receptor in estrogen receptor-negative breast cancer [104]. Also, a small-molecule inhibitor of the amino-terminus domain of the androgen receptor causes regression of castrate-recurrent prostate cancer [105, 106]. Recent discoveries revealed a transcription-independent function of androgen receptor that is essential for prostate cancer cell viability and, therefore, is an ideal target for anticancer treatment. Several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization [107]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273895/