Recent progress in targeting cancer

Zoya N. Demidenko and James A. McCubrey

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Abstract

In recent years, numerous new targets have been identified and new experimental therapeutics have been developed. Importantly, existing non-cancer drugs found novel use in cancer therapy. And even more importantly, new original therapeutic strategies to increase potency, selectivity and decrease detrimental side effects have been evaluated. Here we review some recent advances in targeting cancer.

Keywords: cancer, target, therapy, leukemia, anticancer drugs

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/

When general population discuss today’s medicine, accuracy plays one of the most important roles and people’s lives are directly dependent on it. Hence, any researches related to medicine are necessary to comply with the top standards. The challenge today is that any outcomes of researches can be published online and used as a reference without being properly checked and validated. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this problem and attempted to come up with an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The major principle of this journal is related to Altmetric scores that are used as a quality indicator. That helps both readers and authors to validate publications with Altmetric Article Reports that generate “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a full publications list with respective scores above 100 as well as reports discussed above. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it provides the required help to anyone, who has interest in oncology.

Misha Blagosklonny

“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This article was published back in 2018 by Oncotarget and written by different experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”

The article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are willing to comprehend the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Hereby, the article about melanoma, was used for citations in different news articles 69 times. Besides that, it was referred to in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 

Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This publication has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a brief overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get useful scientific facts. Oncotarget is happy to have the chance to share with online viewers this highly appreciated and high-quality information, that is trustworthy and reliable.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084391/