Current Cancer Therapy Reviews - Volume 5, Issue 4, 2009

Background: A tumor system not only consists of diverse cell types but also comprises all components of action insofar that these components are oriented in terms of diverse cell types. Methods: Thus, it is necessary to decode paradox situations of cellular rationalization, deformation, and communication processes or, in other words, to uncover inconsistencies within tumor cell compartments or distinct topologies of aggregated action effects. Here, a theory may be helpful that discharges into an action-theoretical abstraction and simultaneously includes evolutionary tumor developments. In an evolutionary process, tumor cells may exploit the whole extent of the rationalization features of stroma cells to implement the functional diversity of systems behavior aimed at maintaining homeostasis, and robustness in tumor systems. The introduction of genomic/non-genomic systems-directed therapeutic approaches may allow both, the uncovering of systems topologies of aggregated action effects and the broadening of therapeutic options via systems-directed approaches. Results: (1) Tumor systems biology is now turning into a scientific co-subject. (2) Developing actiontheoretical systems terms with the corresponding conceptual equipment may contribute to the classification of tumor subsystems. (3) Systems-directed therapies may meet new therapeutic requirements, which might help to create therapeutic approaches that are specifically designed for the demand of tumor stages, corresponding systems stages. Conclusions: Therefore, patients would probably not have to be selected according to age and/or co-morbidities because of known adverse toxicities of standard therapies (maximal tolerable doses). In contrast, therapies may meet the (individual) tumor system's characteristics by a systems-orientated selection of biomodulatory acting agents. As shown, toxicities may be modest.

Cytarabine (cytosine arabinoside) is commonly used in the treatment of hematologic malignancies, including both myeloid and lymphoid disorders. The cytotoxic effect of the drug depends on conversion to its triphosphate form in the targeted cells, and the intracellular levels of this active form depend on the balance between phosphorylating and dephosphorylating enzymes. The sensitivity to cytarabine-triphosphate induced cytotoxicity is in addition dependent on the balance between pro- and antiapoptotic signalling in the malignant cells, especially the balance between various members of the bcl-2 family. Even though differentiation induction has been claimed to be important in low-dose cytarabine, most clinical studies suggest that the cytotoxic affect is most important even in this therapeutic strategy. The clinical experience with the low-dose therapy is based on studies in hematological malignancies, mainly acute myeloid leukemia and myelodysplastic syndromes. These studies clearly document the clinical efficiency of low-dose therapy. However, even this low-dose strategy has a risk of severe hematological toxicity and eventually serious or fatal infections especially in elderly patients. Our understanding of the molecular mechanisms behind chemoresistance and chemosensitivity to cytarabine thereby forms the scientific basis for the design of future clinical studies where cytarabine can be combined with new targeted therapy. Low-dose cytarabine may then represent an efficient alternative with an acceptable toxicity even when combined with new anticancer agents in early clinical studies. However, the possibility of pharmacological interactions with the intracellular metabolism of cytarabine by these new agents has to be considered when combination regimens are designed.

The cancer stem cell hypothesis states that tumours arise from cells with the ability to self-renew and differentiate into multiple cell types, and that these cells persist in tumors as a distinct population that can cause disease relapse and hence metastasis. The crux of this hypothesis is that these cells are the only cells capable of, by themselves, giving rise to new tumours. What proportion of a tumour consists of these stem cells, where are they localised, how are they regulated, and how can we identify them? The stromal cells embedded within the extracellular matrix (ECM) not only provide a scaffold but also produce ECM constituents for use by stem cells. Heparan sulfate proteoglycans (HSPGs) are ubiquitous to this cell niche and interact with a large number of ligands including growth factors, their receptors, and ECM structural components. It is still unclear whether ECM degradation and subsequent metastasis is a result of proteases produced by the tumour cells themselves or by cells within the stromal compartment. The identification of the cellular origin of cancer stem cells along with microenvironmental changes involved in the initiation, progression and the malignant conversion of all cancers is critical to the development of targeted therapeutics. As ubiquitous members of the ECM microenvironment and hence the cancer cell niche, HSPGs are candidates for a central role in these processes.

MET is a member of the semaphorins, plexins and MET/RON receptor family, which is stimulated by the ligand hepatocyte growth factor (HGF) and uniquely regulates a wide range of cellular functions. When dysregulated and activated, as in the case of human cancers with MET amplification or overexpression, mutation or alternative splicing, it has been implicated to play pivotal role in human tumor cell progression and metastasis. MET-HGF signal path has been shown to be attractive therapeutic target for human cancer novel therapy. In recent years, substantial progresses have been achieved to advance MET-HGF inhibitory strategies from the bench-top preclinical studies to clinical trial studies. Targeting agents being developed include not only various small molecule MET inhibitors, but also specific anti-MET or anti- HGF antibodies. Current emerging knowledge of the kinases signaling cross-talk networks will eventually facilitate rational design of optimal treatment strategies combining MET inhibition with other inhibitors, such as erlotinib (against EGFR). In this review, we summarize the relevant MET receptor biology, mutations (especially non-kinase domain mutations) and other genomic alterations in human cancers. The strategies to inhibit MET-HGF as novel therapy in human cancer as well as agents undergoing clinical trial studies would be discussed. Finally, we also summarize the various challenges to be met, including predictive biomarkers identification, patient selection, and rational combinational treatment approaches.

Photodynamic therapy (PDT) consists of topical or systemic delivery of photosensitizing drugs followed by irradiation with light. Topical PDT is currently carried out with 5-aminolaevulinic acid (ALA) or methylaminolaevulinate (MAL) both metabolized in the cells to protoporphyrinIX (PpIX), a photosensitizing molecule absorbing visible light. As the rate of ALA-induced PpIX synthesis and accumulation is higher in malignant cells than in normal ones, PDT is able to exert a selective action on neoplastic tissues. PpIX transfers its energy to molecular oxygen generating reactive oxygen species. The subsequent oxidation of lipids, amino acids and proteins together with transcription and release of inflammatory mediators induces cell necrosis, apoptosis and immunemodulation. ALA 20% or MAL 16% (solution or cream) are applied over the skin lesion and then irradiated with blue or red light, depending on the thickness of the tumour. No anaesthesia is needed. Usually two-three treatments are sufficient for actinic keratosis, basal cell carcinoma, Bowen's disease, the main dermatologic indications for PDT. Topical PDT is well suited for lesions that would otherwise require extensive surgical procedures and for patients with contraindications to surgery or with multiple lesions. We review action mechanism, procedures and indications of PDT for non-melanoma skin cancers.

Patients with early stage non small cell lung cancer (NSCLC) have historically been treated by resection alone, with results that have been superior to the results seen with radiation alone. This reflects the selection bias inherent to any comparison of operative and non-operative patients but surgery remains preferred treatment option. However, relapse rate after surgery is significant. In addition, a large proportion of these patients are not amenable to surgery due to medical co-morbidities and co-existing illnesses. These patients typically undergo a course of conventional radiotherapy, which provides poor outcomes both in terms of local control and survival. Attempts at dose escalation have met with some success, but local failures remain common and further dose escalation is limited by unacceptable toxicities. SRT allows for the delivery of a very high dose of radiation to a precise target. SRT presents the challenge of organ motion throughout the respiratory cycle. We review methods to mitigate this problem using both frame-based and frameless techniques, implanted fiducial markers, respiratory gating or deep inspiratory breath hold, and image guidance. Clinical experience with lung SRT continues to grow. Toxicities have been surprisingly mild. Based on available evidence, SRT appears to be effective, convenient and well tolerated.

The understanding of the barriers to effective treatment of cancer is rapidly expanding. As the molecular pathways of apoptosis become better understood, the mechanisms by which cancer cells evade the apoptotic effect of standard chemotherapeutic agents are revealed. Protein kinase B/AKT mediates a potent survival/anti-apoptotic signal when activated; many cancers have been observed to harbor constitutive activation. The mechanism of constitutive activation of AKT in cancer is not usually due to mutation or amplification of the gene, but through activation of upstream signaling events. Extensive preliminary data has shown that inhibition of AKT restores apoptotic sensitivity in various cancers to diverse chemotherapeutic agents, yet the optimal mechanism of inhibition of AKT has yet to be clearly defined. Pancreatic cancer is one of the most difficult to treat given its extreme resistance to the cytotoxic effect of traditional therapy; investigations into therapies to restore apoptotic sensitivity have identified AKT as a potenial target for inhibition. The evolving targeted inhibition of AKT, whether directly or indirectly, is an active area of research with tremendous potential in cancer therapy, and pancreatic cancer specifically, and this field of research is discussed in the current review.

Treatment with thyroid hormone is needed in patients with differentiated thyroid carcinoma (DTC) after the initial treatment (thyroidectomy followed, in most cases, by radioiodine remnant ablation) for two reasons: a) Correction of hypothyroidism in an athyreotic patient (replacement therapy); b) Blockade of thyrotropin (TSH) secretion in view of the TSH-dependence of DTC (TSH-suppressive therapy). Levothyroxine (L-T4) is the hormone of choice, since combination with levotriiodothyronine does not add any clear advantage with respect to L-T4 monotherapy. While replacement therapy obviously is a lifelong requirement, duration of TSH-suppressive therapy depends on the tumor risk stratification after and the response to the initial treatment. According to recent European and American guidelines, in low-risk DTC LT4 treatment should be carried out at TSH-suppressive doses until there is evidence that the patient is disease-free. In high-risk DTC, TSH suppression should be maintained for several years after such an evidence has been achieved. Afterwards, the patient can be shifted to replacement doses, also to avoid the risks of iatrogenic thyrotoxicosis, especially in the elderly and/or in the presence of cardiovascular disease. The dose of L-T4 must be invidualized; particular attention must be given to the coexistence of pathophysiological conditions or drug treatments that may affect L-T4 absorption or metabolism.

The constitutive tyrosine kinase (TK) activity of the Bcr-Abl fusion oncoprotein, the product of the Philadelphia (Ph1)-chromosome, is essential for factor-independent cell proliferation and survival in Bcr-Abl-positive (Bcr-Abl+) leukemias, such as chronic myelogenous leukemia (CML) or Ph1-positve acute leukemias. Currently, Bcr-Abl TK inhibitors (TKIs) such as imatinib mesylate are regarded as the most promising therapeutic strategy for Bcr-Abl+ leukemias, but recent evidence suggests that Bcr-Abl TKIs are unlikely to lead ultimately to complete elimination of leukemic cells. To develop more effective therapeutic strategies for complete leukemia cell elimination, it is essential to understand how cellular life and death decisions are regulated in Bcr-Abl+ leukemias. This paper reviews recent knowledge related to the biologic and molecular regulatory mechanisms for cellular survival and death under Bcr-Abl signaling control in leukemic cells, and focuses on Bcl-2 family-regulated apoptosis, especially on the role of BH3-only proteins, such as Bim, as well as on non-apoptotic programmed cell death, and autophagy. Implications for future therapeutic strategies for Bcr-Abl+ leukemia are also discussed.

There is growing evidence for a role of the hemopoietic microenvironment in the pathophysiology of myelodysplastic syndromes (MDS). Effects of various cytokines on the marrow microenvironment of patients with MDS have been studied. Autoimmunity, i.e. a reaction of autologous T lymphocytes against components of the marrow is also operative in a proportion of patients with MDS. The negative feed-back loop that controls tumor necrosis factor (TNF)α levels in healthy individuals is apparently disrupted in MDS due to auto-amplification signals involving TNFα and interleukin (IL-32). IL-32 mRNA levels in primary adherent cells from patients with MDS are 14- to 17-fold higher than in controls. In contrast, cells from patients with chronic myelomonocytic leukemia (CMML), a myeloproliferative disorder with low TNFα levels, express IL-32 at only 1/10 the level observed in controls. Damage in the microenvironment may occur secondary to oxidative stress, which may also lead to accelerated shortening of telomeres. This is, indeed, true for hematopoietic cells in MDS marrow, but telomere length in marrow stroma does not differ from that in age-matched healthy individuals. Nevertheless, the stroma shows functional aberrancies. Stroma-derived signals facilitate apoptosis in clonal hematopoietic cells but not in normal CD34+ cells. Thus while stroma dysfunction is likely due to signals derived from the hematopoietic clone rather than being intrinsic, it does affect clonal death or survival, respectively. Therefore, signals exchanged between both compartments could serve as targets for therapeutic interventions.