Docetaxel and cabazitaxel are the two taxanes approved for clinical use in CRPC [9, 10]. Docetaxel was the first approved non-hormonal therapy with a demonstrated survival benefit in CRPC. The TAX327 study showed that docetaxel every 3 weeks plus prednisone was superior to weekly mitoxantrone plus prednisone [10]. Median survival in the q3 weekly docetaxel plus prednisone arm was 19.2 versus 16.3 months in the mitoxantrone/prednisone arm [9]. The TROPIC study established the role of cabazitaxel as second-line therapy in CRPC, randomizing men with progressive disease during or after docetaxel to cabazitaxel + prednisone versus mitoxantrone + prednisone [11], and demonstrated 2.4 months improved overall survival with cabazitaxel.

Taxanes function by stabilizing the dynamic polymerization of microtubules. The ability of microtubules to assemble and disassemble is critical for mitosis and thus targeting microtubules preferentially in rapidly dividing cancer cells. Resistance to taxanes may be mediated through overexpression of the multi-drug-resistant P-glycoprotein efflux pump [12], mutations in the microtubule binding sites, and mutations in microtubule-associated proteins giving greater stability to cellular microtubule assembly [13, 14].

Taxanes also affects AR signaling through its alteration of microtubules-associated AR cellular transport and nuclear translocation [15, 16], raising speculation about cross-resistance with AR pathway inhibitors and questions of simultaneous verses sequencing of combinatorial chemo-hormonal regimens. Eigl et al. [17] demonstrated that simultaneous combined taxane-based chemotherapy plus androgen ablation is significantly more effective than the sequential administration of these treatments in the castrate sensitive Shionogi and LNCaP tumor models. Interestingly, a lack of response to castration was observed after initial paclitaxel therapy while gene expression studies confirmed up-regulated of several genes known to play a role in castrate resistance in response to paclitaxel exposure. These findings illustrate how stress-induced gene expression changes after chemotherapy or castration can confer cross-treatment resistance and provide preclinical proof-of-principle for ongoing clinical trials addressing the role and timing of systemic therapies in prostate cancer.

ECOG3805 (CHAARTED) compared standard sequence ADT followed by docetaxel upon castration resistance versus docetaxel given at the start of ADT in 790 men with metastatic castrate sensitive prostate cancer (http://​clinicaltrials.​gov/​show/​NCT00309985). Men received either ADT alone or ADT with the chemotherapy drug docetaxel every three weeks over a period of 18 weeks. Men who received simultaneous combinatorial chemo-hormonal lived longer than patients who received ADT alone with 3-year overall survival of 69.0 versus 52.5 %, respectively (nih.gov/news/health/dec2013/nci-05.htm). Patients with a high extent of metastatic disease accounted for most of the benefit in the overall survival from docetaxel plus ADT (3-year survival rates of 63.4 versus 43.9 % for ADT alone). While further follow-up is needed in order to define the effect of this treatment combination on patients with less extensive metastatic disease, this study provides the first example of clinical efficacy using combinatorial therapies in advance prostate cancer and supports the early addition of docetaxel to ADT rather than waiting until CRPC.

CRPC is a complex process by which cells survive and proliferate in low circulating androgen. This in part involves the reactivation of the androgen receptor (AR) axis [18], by pro-survival genes and alternative mitogenic growth factor pathways [19–22] including the phosphoinositide 3-kinase (PI3K)/AKT pathway. Indeed, the AR (via amplification) and PI3K/AKT (via Pten loss) pathways are the two most frequently activated signaling pathways in prostate cancer. While AR inhibitors confer clinical responses in most patients, PI3K inhibitors rarely induce tumor regression in preclinical models. Indeed, monotherapy with AR or AKT inhibitors result in reciprocal cross-talk activation that helps emergence of acquired resistance [23–26]. For example, Carver et al. [23] showed that these pathways regulate each other via reciprocal negative feedback, such that inhibition of one activates the other. Inhibition of the PI3K pathway restored AR signaling in PTEN-deficient prostate cells in part through relief of negative feedback to HER kinases; conversely, blockade of AR relieves feedback inhibition of AKT through reduced levels of FKBP5 impairing the stability of the phosphatase PHLPP. Hence while tumor cells could adapt and survive when either single pathway is inhibited pharmacologically, combined inhibition of PI3K/AKT and AR signaling using the PI3K/mTOR inhibitor BEZ235 and the AR antagonist ENZ significantly delayed CRPC progression in the LNCaP model [23].

Thomas et al. [27] reported that monotherapy with the AKT-inhibitor AZD5363 increased AR transcriptional activity and AR-dependent genes such as PSA and NKX3.1 expression. These effects were overcome by the combination of AZD5363 with bicalutamide resulting in synergistic inhibition of cell proliferation and induction of apoptosis in vitro, and prolongation of tumor growth inhibition and PSA stabilization in CRPC in vivo. These studies provide preclinical proof-of-concept that combination co-targeting of an AKT inhibitor with an AR antagonist leads to prolonged delay of CRPC progression.

In addition to the AKT pathway, other signaling pathways have been identified that are induced by AR blockade-induced cross-talk activation (Fig. 16.1). For example, AR blockade leads to activation of MAPK pathway which is coordinated by a feed-forward loop involving p90rsk-mediated phospho-activation of YB-1 with subsequently induces the activation of survival pathway leading to the up-regulation of the molecular chaperone CLU, hence inducing treatment resistance [28]. Interestingly, targeting CLU using OGX-011 currently in phase III clinical trials in combination with ENZ not only delay the resistance to ENZ but also inhibit both AKT and MAPK pathways and further provide a preclinical proof-of-principle of co-targeting AR pathway in combination with OGX-011 [28].

In cancer, stress is a driving force behind evolution (oncogenesis) and adaptation (acquired treatment resistance). During transformation, tumor cells undergo drastic shifts in their intracellular and extracellular milieu, frequently exposed to stress microenvironments that include hypoxia, acidosis, nutrient deprivation, and immune attacks from the host. To survive and prosper, like organisms living in the wild, tumor cells must be able to adapt to a variety of stress conditions. Many anti-cancer treatments induce stress responses that inhibit apoptosis and promote emergence of an acquired treatment-resistant phenotype. The heat shock response, for instance, is a highly conserved protective mechanism in eukaryotic cells associated with survival, thermo-tolerance, and oncogenic transformation [29]. Molecular chaperones play key roles in these stress responses, facilitating treatment resistance by regulating protein homeostasis (proteostasis) as well as many signaling and transcriptional survival networks. Chaperones play central roles in endoplasmic reticular (ER) stress [30–32] and the unfolded protein response (UPR), tailored to re-establish proteostasis by inhibiting translation, increasing chaperone expression, and promoting proteasome- and autophagy-mediated protein degradation. While these adaptive responses are cytoprotective, cell death can occur when ER stress and misfolded protein burden overwhelms the degradation capacity of the proteasome or autophagy [33–38]. Co-targeting stress-induced survival pathways regulating proteostasis, such as ERAD or ERAA, may better manipulate cancer cell sensitivity to therapy.

Molecular chaperones, including heat-shock proteins (Hsps), are key mediators of the stress response, acting as genetic buffer to stabilize and help cells cope at times of environmental stress. During cancer progression, Hsps increase Darwinian fitness of cells during transformation, progression, and treatment resistance [39]. Molecular chaperones bind misfolded proteins to facilitate substrate refolding or degradation, protecting cells against protein aggregation, and facilitating refolding or degradation. Chaperone expression is induced after many varied insults including hypoxia, heat shock, anoxia, glucose deprivation, free radicals, carcinogens, hormone therapy, and chemotherapy [40–43]. Indeed, expression of sHSPs is frequently up-regulated in many cancers and correlates with metastases, poor response to chemotherapy, and poor survival.

The transcriptional regulation of sHSPs is convoluted because of redundancy and feedback control, but several stress-related transcription factors are considered to be major inducers of HSPs. Heat shock factor 1 (HSF-1) is a highly conserved transcription factor that binds to consensus heat shock element (HSE) within the promoter regions of HSP genes [44]. Stress-induction of HSF-1 is a multi-step process that involves constitutive expression of HSF-1 monomer, stress-induced HSF-1 serine phosphorylation, followed by its trimerization, nuclear translocation with increased transcription [45]. HSF1 activates the transcription not only for sHSPs but also other molecular chaperones that associate with HSF1 to initiate a negative-feedback loop and inhibit HSF1 transcriptional activity [46]. Deletion of Hsf1 gene in mammalian cells does not alter normal basal expression of HSPs but abrogates stress-induced expression of HSPs [47], suggesting that other transcription factors are involved in the basal expression of HSPs. In mice, HSF-1 deficiency inhibits spontaneous tumor formation initiated by dominant negative mutation of p53 and chemical induced skin carcinogenesis associated with activating mutations of H-Ras proto-oncogene [29]. While HSF-1 is not a classic oncogene capable of driving transformation, it does coordinate a broad of network of cellular functions that supports tumorigenesis, highlighting HSF-1 as key regulator of the stress response that is usurped during oncogenesis to promote adaptation and malignant progression.

This section will review roles for Hsp27 and CLU in stress response and acquired treatment resistance, and their current status as therapeutic target in CRPC.