Clinical Cancer Drugs - Volume 1, Issue 2, 2014

Metastasis is the main cause of death in cancer patients, and in spite of its significance, it is still incompletely understood. In order for cancer to be metastatic, it must undergo a sequence of events, termed as the metastatic cascade. The ability of cancer cells to migrate and invade surrounding tissue is a critical step in the metastasis and is often associated with the formation of specific cellular structures called invadopodia. Invadopodia are actin-based protrusions of tumour cells or transformed cells critically involved in protease secretion and targeting, and cytoskeletal rearrangements enabling cellular invasion. Anti-invadopodia therapy is a possible new field in anti-metastatic treatment. We propose here a novel model for drug discovery of anti-invadopodial compounds based on large scale screening of invadopodia formation in 2D setting followed by validation of the results in complex 3D matrices such as dermis-based matrix.

The nucleation of many breast cancer research projects is the choice of an appropriate model to be used, and a central question to be addressed. Often, a human breast cancer cell line is chosen, and a selection of assays is then employed to test new anti-cancer agents, or to study some aspect of the biology of the disease. Here, we provide a guide for the selection of preclinical models of breast cancer, focusing on commonly chosen cell lines, including MDA-MB-231, MCF-7, BT-474, T47D, and ZR75.1. Important criteria to consider include, among others, the ease of growth of the cells, whether they can form organotypic cultures, their amenability for drug screening assays, whether they are part of the NCI 60 cancer cell line panel, and their array of expression of oncogenes and tumor suppressor genes. Critical to the success of a project may also be whether the model can grow in vivo, and if it can metastasize. The ideal preclinical model is therefore one that permits multiplex in vitro screens as well as complex, orthotopic, animal models that replicate aspects of late stage disease. Additional criteria to consider include proprietary restrictions of some cell lines, which may later hamper drug development, and whether the models comply with institutional guidelines, as well as the possibility of incorporating molecular markers that allow for the in vivo non-invasive monitoring of disease. We provide practical examples to illustrate the challenges and the solutions to developing breast cancer projects, including studies on the treatment of metastatic disease using metronomic chemotherapy, either alone or in combination with anti-Her-2 targeting strategies, such as trastuzumab and pertuzumab.

In the present review we report the preclinical development of paclitaxel-based combination treatment with antiangiogenic drugs and their translation into clinical practice. A particular attention is paid to the mechanisms by which an interaction between paclitaxel and antiangiogenic drugs may be advocated. In mid ‘90s, the discovery of the antiangiogenic properties of paclitaxel has widened the possible uses of the drug for the treatment of solid tumors. In fact, paclitaxel is able to negatively modulate vascular endothelial growth factor (VEGF) and angiopoietin-1 expression, whereas the drug may induce an increased expression of the antiangiogenic endogenous modulator thrombospondin-1. On the basis of these discoveries, several promising antiangiogenic treatments have been identified in preclinical models, in which paclitaxel has been administered together with direct antiangiogenic drugs (i.e., bevacizumab and vandetanib). In other cases, the paclitaxel-based combination included inhibitors of those mediators whose activity is associated with and supports neovessel formation, such as matrix metalloproteinases, cyclooxygenase-2 and endothelin-1. The synergistic cytotoxic effect of combined treatments may depend on the capability of paclitaxel to inhibit both tissue invasion by tumors (i.e., antagonizing matrix metallo-proteinase activity) and secretion of pro-angiogenic mediators (i.e., VEGF) through an antagonistic effect of the taxane against endothelin-1/endothelin A receptor. Some of these combination treatments have not yet (or will not) reach clinical studies and the therapeutic armamentarium, despite the promising results achieved in preclinical models. However, they may play a role as proof-of-concept in the growing knowledge and interest in the mechanism by which we can modulate or halt angiogenic processes driven by tumors.

Low-dose metronomic (LDM) chemotherapy was developed to overcome resistance to standard, maximum tolerated dose (MTD) chemotherapy by shifting the primary treatment target from the highly adaptive tumor cells to diploid endothelial cells. As such, LDM chemotherapy exerts potent antiangiogenic effects. However, it became rapidly apparent that LDM chemotherapy is subject to resistance on its own, albeit by distinct mechanisms compared to MTD chemotherapy. To address the lack of detailed knowledge on the mechanisms of resistance to LDM chemotherapy, we decided to analyze the characteristics of prostate and breast cancer models with stable acquired resistance to LDM cyclophosphamide (CPA). Whereas our studies suggest that compensatory angiogenic activity does not account for such resistance in a major way, we identified low autophagic activity of tumor cells to be associated with resistance to LDM CPA. In addition, autophagy inhibition by using chloroquine in the PC-3 human prostate cancer model, or genetically engineered autophagy deficiency in immortalized baby mouse kidney cell tumors reversed the antitumor effects of LDM CPA. These findings contrast with observations from others showing that autophagy inhibition might enhance the antitumor effects of vascular endothelial growth factor (VEGF) targeted antiangiogenic therapy. On the other hand, the impact of autophagy modulation in cancer is known to be highly context-dependent. Since a subset of malignancies is expected to have intrinsic autophagy defects, assessing the autophagy status of tumors may become a tool to select patients for VEGF pathway targeted versus LDM antiangiogenic therapy.

Recent studies have shown that certain genetically modified tumour cells are extremely sensitive to the effects of PARP-1 inhibition without the need for the presence of a cytotoxic agent leading to selective cell death. For example BRCA1 and BRCA2, which are components of the homologous recombination DNA repair pathway, are deleted in 5- 10% breast cancer patients and have showed that PARP-1 inhibitors are highly effective agents as monotherapy. These results indicate that for cancer treatment, the PARP inhibitors, whether as individual agents or in combination with chemotherapeutics or as potential monotherapies, could be of significant therapeutic importance. Previous investigators have designed inhibitors of PARP-1 to mimic the substrate-protein interactions of NAD+ with the enzyme. Mechanistically, these compounds inhibit PARP-1 by blocking and binding to the substrate, particularly the nicotinamide moiety, to the active site of the enzyme. Early weak inhibitors such as 3-aminobenzamide have been developed into more potent PARP-1 inhibitors derived from a range of related pharmacophoric templates. Further lead optimisation focussed primarily on enhancement of pharmacokinetic properties has afforded orally available PARP-1 inhibitors for use either in combination or with existing cytotoxics or as a monotherapy in target tumour types. The current review gives an idea about the role and applications of PARP in cancer therapy. This review discusses molecular modelling strategies and synthetic applications so far reported. The author also discusses how SAR can yield new PARP inhibitors with lesser side effects.