Topics in Anti-Cancer Research

Multiple Myeloma (MM) is a complex disease considered incurable in the majority of patients; however, several new treatments have been developed over the last decade, including third generation immunomodulatory drugs (pomalidomide), second generation proteasome inhibitors (carfilzomib and ixazomib), a histone deacetylase inhibitor (panobinostat) and monoclonal antibodies (elotuzumab and daratumumab). In addition, some new agents with unique mechanisms of action are in the process of development. Of these, isatuximab, oprozomib, filanesib (ARRY-520), dinaciclib, venetoclax, selinexor, melflufen and LGH-447 are the most promising, demonstrating preclinical single-agent activity against MM. In this chapter, we present the current status of newer and investigational anti-myeloma agents, and outline future directions for clinical use. We also summarize recent developments in the treatment of MM patients, obtained through a thorough literature review of all WO, EP and US patents filed in 2010-2018, using PubMed and http://ep.espacenet.com/ as sources. The development of novel drugs will hopefully lead to therapies with more potent effects.

In the early 1940's, the US Food and Drug Administration (FDA) approved marketing of synthetic estrogens; non steroidal Diethylstilbestrol (DES) and Ethinylestradiol (EE) as well as Conjugated Equine Estrogens (CEEs) for medical purposes. High Dose Estrogen (HDE) therapy using DES and EE was introduced into the treatment of advanced breast cancer in postmenopausal women. Oral contraceptives (OCs) comprising EE were developed in the early 1960s and EE became a standard component of near all combined forms of contraceptive pills. Use of exclusively synthetic estrogens for both HDE therapy of breast cancer and contraception ensured a possibility for clear evaluations of the risks and benefits of synthetic hormone use. HDE therapy for breast cancer induced serious toxicity affecting near all organs, suggesting a genome-wide disturbance in cellular mechanisms. OCs comprising low doses of EE which may induce arterial and venous thromboembolic events and show ambiguous correlations with cancer risk at different sites by means of altered regulation of Estrogen Receptors (ERs). In contrast, for menopausal Hormone Replacement Therapy (HRT) both synthetic and natural estrogens extracted from biological samples were prescribed. Among postmenopausal women, the use of estrogens with different origin and even their combinations with synthetic progestins resulted in a chaos of quite controversial clinical experiences concerning the risks for arterial and venous thromboembolism and for cancers of breasts and endometrium. Analysis of the effects of specific HRT types in postmenopausal women justified that horse urine derived CEE without synthetic progestin is a highly beneficial formula against breast cancer, coronary heart disease and bone loss. The presented study reveals that an 80 year period of synthetic hormone prescription may be blamed for the misbelief that ERs exposed to elevated endogenous estrogen concentrations may be deregulated and drive cancer promoting changes. In tumors constitutively upregulating ER alpha expression, recent patents disclose amplifying ESR1 mutations.

Phenazines are nitrogen-containing heterocycles which possess a wide range of biological activities and in particular, cytotoxic effects. Moreover, various phenazines have been prepared having alkyl, amide, carboxylic acid, aldehyde, and pyrano groups. These synthetic phenazines possess significant anticancer effects towards various cancers. On the other hand, only a few natural phenazines have been reported with anticancer effects. This chapter presents a comprehensive overview of the most recent patents related to the phenazines as anticancer agents.

Cancer Stem Cells (CSCs) are those tumour cells, which possess the ability to self-renew, form a new tumour, produce progeny of multiple phenotypes and are responsible for maintaining the growth of the tumour. CSCs have different gene expressions and signalling pathways compared to other tumour cells. The mutation in the CSC gene is the main reason for cancer initiation, progression, metastasis, recurrence and drug resistance. Hence, targeting the CSCs selectively can cure the disease without much damage to the healthy tissues caused by traditional chemotherapy and radiotherapy. Previous works have shown various therapeutic strategies for cancer using new drugs molecules, nanomedicines, specific surface markers of CSCs, modulators of signalling pathways, agents for adjustment of the microenvironment signals, drug-efflux pump inhibitors, manipulators of miRNA expression, inducers of CSCs apoptosis and differentiation. A few selective novel compounds and therapeutic strategies targeting CSCs are presently in preclinical and clinical trials. This chapter highlights the novel strategies targeting CSCs for the successful treatment of cancer. The challenges in the development of new strategies leading to the eradication of cancer and recent patents issued in the area of CSCs targeting are also discussed.