Frontiers in Anti-Cancer Drug Discovery

Despite the great efforts made in research into cancer, in the last two decades therapeutic progress has unfortunately been very limited. It is crucial to seek new avenues of enquiry able to provide solutions to this scientific challenge. Currently, the term “Magic Bullet”, coined by Paul Ehrlich, should be revisited and applied to new, more selective and effective cancer treatments. The peptide substance P (SP) exerts an important role in cancer progression. After the binding of SP to the tachykinin neurokinin-1 receptor (NK-1 receptor), the peptide exerts a mitogenic action on tumour and endothelial cells (inducing angiogenesis). It also regulates the migration of tumour cells and exerts an antiapoptotic effect on them. However, when NK-1 receptor antagonists bind to NK-1 receptors, these antagonists block the functions regulated by SP. These antagonists inhibit tumour cell proliferation (tumour cells die by apoptosis), angiogenesis, and tumour cell migration. These antagonists are broad-spectrum antitumour drugs. It is known that the administration of NK-1 receptor antagonists in combination with cytostatics exerts a synergic effect and decreases the side effects induced by cytostatics to a considerable extent. Many authors have suggested that these antagonists should be called “Intelligent Bullets”, because cancer cells overexpress the NK-1 receptor and hence NK-1 receptor antagonists could act as specific anticancer drugs. The aim of the present study is to update knowledge of the involvement of the SP/NK-1 receptor system in cancer progression. We also suggest the use of NK-1 receptor antagonists as an anticancer therapy.

Until no far past, advanced hepatocellular carcinoma (HCC) was considered as an “orphan” disease in terms of effective molecules when compared with other highly prevalent cancers worldwide. Recently, HCC -a tumor renowned to be refractory to systemic chemotherapy- has attracted wide interest as a result of improved understanding of its molecular biology and pathogenesis. HCC is a well-vascularized tumor in which angiogenesis is strongly implicated for aggressiveness and dissemination and targeted drugs (mainly angiogenesis inhibitors) have been tested to block neovessels and various signaling pathways involved in this disease. This approach has been successful, at least for sorafenib -an antiangiogenic and multikinase inhibitoracross 2 large international randomized phase III trials confirming the efficacy and safety of this compound as validated option in patients with advanced-stage HCC.

Approval of sorafenib as the new standard care for advanced HCC raised the interest to investigate plethora of drugs in this pathology and in different setting including earlier stages, and as adjuvant therapy. Currently, several small molecules and antiangiogenic agents are investigated in preclinical and clinical studies with disparate outcomes, with the hope to identify new efficient therapies, thereby opening new prospects but also raising several unmet needs.

This review develops the rational for using these emerging drugs in treatment algorithm of HCC, and highlights the strength and limits of novel compounds with focus on specific challenges for their clinical development.

The contribution of metal compounds to oncology is well-known due to the clinical relevance of cisplatin drug and its analogues in current Platinum Cancer Chemotherapy. The undesirable drawbacks, e.g., limited range of treatable cancers, tumor resistance and serious side-effects, associated to the use of platinum drugs, nevertheless, account for the developing of new alternative metal-based anticancer drugs. A number of promising ruthenium compounds exerting anticancer/antitumor activities has been reported in the last decades and significant progress was achieved with the entrance of the anti-metastatic NAMI-A and the cytotoxic KP1019 (and its analogue KP1339) Ru(III) compounds into human clinical trials. Selected Ru-based drugs considering the diversity of structures and oxidation states as well as the distinctly different chemical, biochemical and pharmacological activities (e.g., anti-metastatic or cytotoxic activities in tumors) are discussed in this chapter, updating the 2010 review by the same author. The two classical Ru(III)-based drugs and different families of Ru(II)- organometallics are presented. The chapter includes also the novel class of diruthenium(II,III)-(pharmaceuticals) metallodrugs, with focus on Ru₂(II,III) metal-metal bonded cores coordinated to ligands derived from pharmaceuticals such as nonsteroidal anti-inflammatory drugs or the γ-linolenic acid, targeting glioma cancer therapy.

The development of chemotherapy or endocrine therapy has improved survival in patients of breast cancer. At the same time, molecularly-targeted therapy is also an important strategy. Molecularly-targeted therapeutic strategies is an effective for breast cancer, and clinical studies have shown its potential molecular targets which include human epidermal growth factor receptor (HER), mammalian target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF). However, therapy for recurrence or metastatic patients is still palliative, and the possibility of inducing complete cure for breast cancer remains remote. For this reason, many new drugs and therapeutic strategies have been investigated. Here, we reviewed the up-to-date basic and clinical developments in molecularly-targeted therapy for breast cancer, focusing on HER, mTOR, and VEGF.

Multiple, pleiotropic functional traits are acquired by transformed cells during progression to the neoplastic state. These include genomic instability with several defined mutations that are associated with uncontrolled proliferation, resistance to cell death with induction of immortality, altered cellular metabolism, loss/inactivation of tumor suppressor responses, evasion of immune surveillance, induction of angiogenesis with vascular perturbation, and activation of cell invasiveness resulting in metastasis. A better understanding of any overlapping pathogenetic mechanisms underpinning several of these properties would facilitate development of novel and more effective modalities to treat cancer. Dissecting out the molecular basis for these unique properties of malignancy has already resulted in the discovery and development of novel anticancer drugs.

Extracellular nucleotides and nucleosides have been recently identified as crucial signal mediators in the tumor microenvironment and are known to specifically interact with purinergic receptors. These cellular activation processes provoke different intracellular signaling transduction pathways, termed as “purinergic signaling”. Ectonucleotidases, especially those of CD39/ENTPD family, regulate pericellular levels of proinflammatory adenosine 5'-triphosphate (ATP) to ultimately generate antagonistic antiinflammatory nucleosides such as adenosine thereby tightly modulating purinergic signaling. Such regulated cascades of purinergic signaling have been shown to participate in many of the above fundamental pathophysiological processes in the context of inflammation and immune responses within the tumor microenvironment.

In this chapter, we review several purinergic mechanisms involved in cancer. We specifically highlight the discovery and development and the potential uses of drugs targeting ectonucleotidases that would be applicable to cancer therapy. We further discuss recent advances using purinergic modulation in cancer therapy and consider several of the therapeutic obstacles that would need to be overcome.

HER2 is overexpressed in approximately 20-25% of breast cancers and defines an aggressive sub-type of the disease. Fortunately for patients with HER2 positive breast cancer, the prognosis has improved in the last 10 years due to the development of HER2 targeted therapies, in particular trastuzumab, the HER2-directed monoclonal antibody. Recent data show that approximately 9.5% of patients with HER2 positive metastatic breast cancer achieve a durable complete response (> 5 years) following trastuzumab-based therapy. However, 90% of these patients still continue to develop progressive disease. These data highlight the need to develop novel therapeutic strategies to overcome both innate and acquired resistance to HER2 directed therapeutics.

Lapatinib, a small molecule tyrosine kinase inhibitor of HER2 and EGFR, has efficacy in trastuzumab resistant breast cancer and is approved for the treatment of patients with trastuzumab-refractory HER2 positive metastatic breast cancer. However, in metastatic disease, therapeutic action is often short-lived with most patients developing progressive disease. Thus, HER2 positive tumors can be innately resistant, or acquire resistance, to both trastuzumab and lapatinib.

Over the past 2 years, two new HER2 targeted therapies, pertuzumab and T-DM1 have received approval for the treatment of HER2 positive metastatic breast cancer. The pertuzumab monoclonal antibody blocks dimerization of HER2 with other members of the HER family and clinically has been shown to improve overall survival when used in combination with trastuzumab and docetaxel. The novel antibody drug conjugate, T-DM1, which links trastuzumab to the cytotoxic agent emtansine, improves the response of patients with trastuzumab-refractory metastatic breast cancer, compared to the standard of care lapatinib plus capecitabine regimen. A number of second generation irreversible pan-HER tyrosine kinase inhibitors are currently in clinical development, including neratinib, afatinib and dacomitinib.

More recently, the utility of HER2-directly therapeutics has been expanded into nonbreast tumors such as gastric cancers that carry the HER2-alteration. Data from ongoing clinical trials will determine if targeting HER2 can also improve the prognosis of these cancer patients.