Vincent C. O. Njar

Aromatase inhibitors and their application in breast cancer treatment

Estrogens are known to be important in the growth of breast cancers in both pre- and postmenopausal women. The number of breast cancer patients with hormone-dependent disease increases with age, as does the incidence of breast cancer. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. Because aromatase catalyzes the rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme have been developed in the last few years as a logical treatment strategy. Two classes of aromatase inhibitors, steroidal and nonsteroidal compounds, are now in use. Among the steroid substrate analogs, formestane and examestane have been shown to be effective in breast cancer patients with advanced disease. Highly potent and selective nonsteroidal inhibitors have recently been found to suppress plasma and urinary estrogens by more than 95% in breast cancer patients. Two of these compounds recently were approved in the United States and have been shown to be more effective than other second-line agents in terms of overall response rates and treatment failure, as well as better tolerated. Although studies of the efficacy of these agents in earlier stage disease are awaited, it is evident that aromatase inhibitors can extend the duration of treatment in breast cancer patients.

Comprehensive pharmacology and clinical efficacy of aromatase inhibitors.

The goal of hormone therapy is to deprive breast tumours of estrogens, since estrogens have been implicated in the development or progression of tumours. This can be accomplished by the use of antiestrogens that block estrogen action or by inhibiting aromatase, the enzyme that catalyses the final and rate-limiting step in estrogen biosynthesis.A number of steroidal and nonsteroidal compounds have been developed as aromatase inhibitors. This review highlights the valuable role that a few of these aromatase inhibitors have played, and continue to play, in the treatment of breast cancer. Following background information regarding the biochemistry of aromatase, the rationale for its inhibition, and an outline of the test systems for evaluating and characterising aromatase inhibitors, the discussion focuses on the new generation of aromatase inhibitors that are in clinical trials or clinically available Specifically, it discusses the pharmacology and clinical efficacy of formestane, exemestane, rogletimide, fadrozole, vorozole, anastrozole and letrozole.The role of these agents as the optimal second-line agents (after tamoxifen) for the treatment of advanced breast cancer has been established; their prospects in other clinical settings and as potential breast cancer chemopreventives are warranted but are yet to be fully determined.

Prostate Cancer: Current and Emerging Therapies

Prostate cancer (PC) is the second most prevalent cause of death in men in the USA and Europe. The dependence of PC on androgens has been recognized for more than 7 decades. Medical and surgical androgen deprivation therapy (ADT) has been a standard palliative therapy for metastatic PC. However, an estimated 217,730 new cases and 32,050 PC related deaths in the USA alone in 2010 despite ADT, make the need for finding new targets and novel therapies an absolute priority [1]. Despite medical treatment, the vast majority of patients with metastatic prostate cancer inevitably progress and die from their disease. While initially majority of metastatic prostate cancers rely on the availability of androgens for growth and survival, in their final stages of disease, these patients eventually progress clinically under androgen-deprived conditions. Under the selective pressure of drug treatment, prostate cancer cells are then able to acquire molecular changes that allow them to survive androgen-deprived conditions, gain a selective growth advantage, and finally, result in progression of disease. Our knowledge about this disease is increasing. However, the cellular and molecular events that are necessary to cause progression of prostate cancer from an androgen-dependent (AD) to an androgen-independent (AI) state of disease are not completely understood. With a 9% response rate, chemotherapy was once thought to play a clinically insignificant role in metastatic and castration resistant prostate cancer (CRPC) [2]. More recently, however, a role has emerged for systemic chemotherapy after the demonstration of a small but significant survival benefit for taxane-based chemotherapy in the two landmark studies, TAX-327 and SWOG-9916 [3, 4]. Since median survival for patients with metastatic CRPC is still only about 18 months, there is plenty room for further improvement. Moreover, there is a strong need for second and third-line regimen for patients progressing after docetaxel, and these patients should be enrolled into clinical trials.

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.