Current Cancer Therapy Reviews (v.10, #3)

Comparative Analysis of Current Modality of Therapy in Head and Neck Squamous Cell Carcinoma Correlating the Expression Level of p38α by Kamaldeep Gill, Rahul Kumar, Abhishek Gupta, Bidhu Kalyan Mohanti, Sharmistha Dey (219-224).
p38α MAPK, a key therapeutic target in HNSCC can be considered as a prognostic marker and is implicated in response to radiation-therapy (RT). We compared the outcome of treatment viz. RT (group-I) and concurrent-RT (combination of RT with chemotherapy or surgery, group-II) with respect to p38α MAPK in HNSCC. The case-controlled study was performed on 143 HNSCC patients. From these p38α estimation was done thrice only for 104 patients (52 each in group-I and II), at pre, during and post-therapy periods using surface Plasmon resonance (SPR) technology, ELISA and western blot analysis. In HNSCC the over-expressed p38α levels declined after treatments in both the groups. The patients receiving only RT had a lower p38α level than those treated with concurrent-RT (p=0.009). Hence, p38α was found to be responsive to RT in HNSCC and it may be useful in predicting the treatment outcome and further improve the prognosis of disease in addition to clinical parameters.

HER2-targeted Therapeutic Strategies for HER2-positive Metastatic Breast Cancers by Teruhiko Fujii, Keisuke Miwa, Tomoyuki Ushijima, Mototsugu Matsunaga, Masaru Fukahori, Kotaro Yuge, Uhi Toh, Nobutaka Iwakuma, Ryuji Takahashi, Hiroki Takahashi, Miki Takenaka, Mai Mishima, Yoshito Akagi, Masayoshi Kage, Shino Nakagawa (225-233).
The development of effective chemotherapy or endocrine therapy has significantly improved survival among patients with breast cancer, and recently molecular cancer therapeutics is emerging as another new approach. The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases is an attractive target for anticancer strategies. Trastuzumab is a humanized monoclonal antibody that binds directly to domain IV of the extracellular region of HER2, suppressing HER2 signaling activity, and marking tumor cells that overexpress HER2 for further immunological attack through antibody-dependent cellular cytotoxicity (ADCC). Trastuzumab is a key drug in the treatment strategy for HER2- positive breast cancer in neoadjuvant, adjuvant and metastatic diseases. However, a significant proportion of HER2- overexpressing breast cancer patients either do not respond or eventually become resistant to trastuzumab. For this reason, numerous new agents and therapeutic strategies are under investigation. Lapatinib is an oral small-molecule tyrosine kinase inhibitor (TKI) that reversibly and selectively inhibits both HER1 and HER2, and findings suggest that lapatinib is a potential therapeutic for breast cancer patients who are resistant to trastuzumab. Other agents, such as pertuzumab or TDM1, have shown promising results in clinical trials of breast cancer. Furthermore, strategies combining multiple HER2- targeted therapies might offer additive or synergic effects, and lead to improved outcomes. Here we describe the latest preclinical and clinical developments in HER2-targeting therapeutic strategies for breast cancer.

Thermodynamics and information Physics Offer New Opportunities in Cancer Therapy by Joseph Molnar, Barry S. Thornton, Peintler Gabor (234-245).
The change of the entropy is the arrow of understanding spontaneous processes in complex systems. The entropy production is the sum of several entropy flows resulting in collective entropy, which determines the direction of individual entropy flows in a biological system. In case of cancer patients these thermodynamical terms have a key role in the tumor development on the expense of the host integrity. The life develops towards the entropy minimum, but cancer tends towards entropy maximum. The relationship between entropy and information quantity was discussed in general by Schrödinger in 1948 and Prigogine [1, 2]. Thermodynamic differences between solid tumors and surrounding normal tissues were promising objects to follow the direction of entropy flow between normal and cancerous tissues. Cancer development is an exergonic process, heat flows from tumor to its surroundings forcing to surrounding normal tissues to gain heat. The differences in the fluxes of entropy produced by various components define the interaction and direction of entropy flow between tumorous and healthy tissues. Tumor cells always have higher entropy than normal cells. Normal, healthy cells develop toward the entropy minimum, whereas the entropy production of cancer cells proceeds towards the entropy maximum. Entropy production rate is the result of bidirectional currents, the sum of individual fluxes flowing in opposite directions between cancerous and normal tissues in the open system. The irreversible processes communicated via various dissipation mechanisms are driven by differences in heat production, chemical potential gradients, Gibbs energy, intracellular acidity, conductance, membrane potential gradients, membrane potential of cells and the response to the exposure to external force fields. The rate of entropy production of tumors is always higher than that of healthy tissues. The response in entropy production of normal and tumorous tissues to applied external forces is different. Consequently, the exposure of a tumorous area to external energy may reverse the direction of the entropy-current-mediated flow of information between the tumor and its environment. In this paper the differences between normal and cancerous tissues will be analyzed on the basis of a comparison of the direction of various components of entropy flow. When the entropy production of the normal tissues is increased by a particular external force so as to be above the entropy of the cancerous tissues, the newly achieved higher entropy of the healthy tissue mediates the signal transmission of normal tissue- to the cancer cells. The process can lead to possible new strategies in the therapy of solid tumors. The expansion of the tumor mass into normal tissues in an intimate relationship provides certain advantages as concerns the survival and growth for normal tissues over that of tumorous tissues. In this process the following mechanisms should be considered: the modification of energy production, glucose oxidation, pH, and the membrane potentials by means of external forces etc. It is presumed that some type of external forces can reduce the entropy flow as a carrier of information flow from cancerous tissues to normal tissues. We suppose that the second law of thermodynamics allows to change the direction of informational entropy from co-existing tumorous tissues to normal tissues by specific external forces. The direction of some components of entropy flow can be reversed. Thermodynamics is essential for an understanding of the processes maintaining the living state and conditions resulting in weak links in biological processes, leading to various diseases. The mechanism of cancer development may involve a thermodynamic explanation, where a series of effects induce disorder in healthy tissues. The process is characterized by the conversion of order to chaos in the exposed tissues that survive as a parasite of the host. Differences between development of healthy and tumorous tissues result in an unidirectional-way for the tumor growth, which evolve towards the entropy maximum following the second law of thermodynamics. Our paper will focus on aspects of and entropy production-related information flow in tumorigenesis and driving forces for cancer growth in the host. We suggest that the results of a thermodynamic comparison of tumor progression and conditions of sustaining healthy tissues will help in the design of novel strategies for cancer therapies.

Potentials of Hydrogels in Cancer Therapy by Prem Prakash Sharma, Ravindra Kumar, Anil K Singh, Brajendra K Singh, Ajay Kumar, Brijesh Rathi (246-270).
Hydrogels have emerged as an unique and potential transporters for the target drug delivery systems in cancer therapy. Cancer is a terrible disease extracting toll on human health across the world probably due to several drawbacks of the conventional cancer treatments. However, hydrogels facilitate the modern and improved prospects for the treatment of cancer with minimum cytotoxic effects to the healthier cells or tissues. Besides, the easy tailoring associated with the structural features and high biocompatibility of hydrogels have attracted enough attention and offer them as a strong tool for the development of nanomedicine. This review is devoted to update the current studies related to hydrogels and their applications as vectors for cancer chemotherapy.

MicroRNAs in Cancer Gene Therapy: Another Look by Igor V. Korobko (271-276).
Abnormalities in microRNA expression in tumor cells are widely used as a basis to develop novel therapeutic and diagnostic approaches in oncology. The former mostly aims to target oncogenic microRNAs or to restore expression of microRNAs with tumor suppressor properties in cancer cells. However recently another way of using specific microRNA loss in tumor cells has been suggested. The strategy relies on frequently lost in cancer cells but abundant in cell of normal tissues specific microRNAs, and aims to control unwanted expression of a gene essential for therapeutic action, either therapeutic transgene or essential for viral replication gene in oncolytic viruses, thus minimizing damage to normal tissues and improving safety of cancer gene therapy. Here, history of development and basic principles of the approach as well as current progress in the field are overviewed, with emphasis on benefits brought by the microRNA-based control of specificity for cancer gene therapy and emerging possibility of personification of treatment.

Hepatocellular Carcinoma Outside of the Milan Criteria by C. Anne Doughtie, Michael E. Egger, Kean O. Feyzeau, Christopher M. Jones, Michael R. Marvin, Kelly M. McMasters, Eric G. Davis (277-283).
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide and the incidence and mortality rate are nearly identical in the United States. The Milan Criteria established thresholds of tumor size and number as predictors of optimum overall survival with liver transplant and changed the definitive treatment for HCC. However, after nearly two decades of experience two problems have emerged: post-transplant recurrence continues and an increasing number of patients exceed these size criteria. While tumor burden is an important prognostic factor, it remains limited in its ability to fully define underlying tumor biology and predict recurrence after transplant. Recognizing that tumor size and number are merely surrogate markers of tumor behavior, multiple centers have sought to expand these criteria and consider other oncologic and radiologic factors. Response to locoregional therapies may help to better determine tumor behavior and predict which patients might recur after transplant. Emerging analysis of tumor biology and genetics may also help to predict recurrence more accurately than size alone. Future selection of transplant candidates may be via molecular profiling or chronological imaging changes to identify those patients who would benefit most from the finite number of available grafts, while limiting recurrence after transplant.

Non-small cell lung cancer (NSCLC) accounts for more deaths than any other cancer. Treatments are limited, and prognoses are usually very poor. Amitripyline is a tricyclic antidepressant with multiple effects which may give a variety of benefits to lung cancer patients. Effects on pain, mood, and sleep are of clear potential benefit and are well established, whereas effects on cough and respiratory function are currently under investigation. In addition, potential antitumour effects have yet to be comprehensively tested. Beneficial effects are limited by dose dependent toxicity and adverse effects. Nevertheless, amitriptyline appears to have place in the management of lung cancer and warrants further investigation.