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Oral cancer is one of the most common cancers in the world and India. Signaling molecules play an important role in Oral Squamous Cell Carcinoma (OSCC). PI3K and EGFR signaling molecules are known to be deregulation in most cancers including oral cancer. These are associated with oral cancer progression and drug resistance. PI3K and EGFR signalling molecules have been linked to the examined resistance developed to radiation and chemotherapy. Crucial signaling molecules that function downstream of the survival pathways, particularly at points where several of these pathways crosstalk that development oral cancer and drug resistance. The main focus of this review is to discuss the role and regulation of PI3K and EGFR in oral cancer drug resistance.

Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the effects of pharmacological A2AR and A1R activation. The A2AR agonist CGS21680 protected the primary steatotic murine hepatocyte from IR damage and the activation of ASK1 and JNK. Such an effect was attributed to a phosphatidylinositol-3-kinase (PI3K)/Akt-dependent inhibition of ASK1. By contrast, the A1R agonist CCPA enhanced IR damage, intracellular steatosis and oxidative species (OS) production, thereby further increasing the lipid/OS-dependent ASK1-JNK stimulation. The CGS2680 and CCPA effects were nullified by a genetic ASK1 downregulation in steatotic hepatoma C1C7 cells. In steatotic mice livers, CGS21680 protected against hepatic IRI and ASK1/JNK activation whereas CCPA aggravated hepatic steatosis and IRI, and enhanced ASK1 and JNK stimulation. These results evidence a novel mechanism of CGS21680-mediated hepatoprotection, i.e., the PI3K/AKT-dependent inhibition of ASK1, and they show that CGS21680 and CCPA reduces and enhances the IRI of fatty liver, respectively, by preventing or increasing the activation of the cytotoxic ASK1/JNK axis. They also indicate the selective employment of A2AR agonists as an effective therapeutic strategy to prevent IRI in human fatty liver surgery.

Metazoan living cells exposed to microgravity undergo dramatic changes in morphological and biological properties, which ultimately lead to apoptosis and phenotype reprogramming. However, apoptosis can occur at very different rates depending on the experimental model, and in some cases, cells seem to be paradoxically protected from programmed cell death during weightlessness. These controversial results can be explained by considering the notion that the behavior of adherent cells dramatically diverges in respect to that of detached cells, organized into organoids-like, floating structures. We investigated both normal (MCF10A) and cancerous (MCF-7) breast cells and found that appreciable apoptosis occurs only after 72 h in MCF-7 cells growing in organoid-like structures, in which major modifications of cytoskeleton components were observed. Indeed, preserving cell attachment to the substrate allows cells to upregulate distinct Akt- and ERK-dependent pathways in MCF-7 and MCF-10A cells, respectively. These findings show that survival strategies may differ between cell types but cannot provide sufficient protection against weightlessness-induced apoptosis alone if adhesion to the substrate is perturbed.

Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties and also contribute to systemic changes that influence physiologic responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via upregulating expression of endothelial lipase in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid–mediated pathways, but also promotes survival by stabilizing antiapoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event that further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge. Significance: The studies presented herein demonstrate that the liver provides a microenvironment in which leukemia cells acquire unique metabolic properties. The adaptations that occur in the liver confer increased resistance to chemotherapy. Therefore, we propose that therapies designed to overcome liver-specific metabolic changes will yield improved outcomes for patients with leukemia. This article is highlighted in the In This Issue feature, p. 211

Photothermal therapy (PTT) is an externally activated approach that generates heat to damage, repair, or modulate biological targets. Gold nanoparticles (GNPs) combined with PTT provide unique opportunities for biomedical applications, where light activation can trigger both direct heat-mediated cytotoxicity and the release of drug payloads from nanoparticles. The combination of PTT and other cancer therapies, based on interactive mechanisms that target multiple nonoverlapping growth and survival pathways, is key to improving treatment outcomes. With advances in the development of GNPs and miniaturized light delivery systems, PTT can now access diseases at hard-to-reach anatomical sites in our body. This section introduces engineering aspects interfacing PTT and GNPs, as well as their preclinical and clinical applications in therapy, surgery, and diagnosis.

Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways. Many of these strategies involve downregulation of Mcl-1, a pro-survival Bcl-2 family member that is not targeted by venetoclax, and which often confers resistance to this agent. Given encouraging clinical results involving venetoclax in both lymphoid and myeloid malignancies, it is likely that such combination approaches will be incorporated into the therapeutic armamentarium for multiple hematologic malignancies in the near future.

Background In high risk pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients, gain of function mutations and translocations affecting JAK2 have been described. These mutations and translocations result in aberrant kinase signaling and may therefore serve as an ideal target for precision medicines. Aim Evaluate the frequency and prognosis of JAK2 lesions among different subtypes of childhood BCP-ALL, and study the efficacy of the JAK1/2 inhibitors momelotinib and ruxolitinib. Methods This study comprised 77 BCR-ABL1-like cases and 76 B-other cases which were screened for JAK2 translocations using RT-PCR. Furthermore a representative pediatric cohort of 461 newly diagnosed BCP-ALL cases was screened for JAK2 mutations using targeted next-generation sequencing. Clinical analyses were performed in 341 BCP-ALL patients. Patient-derived-xenograft (PDX) cells were isolated from NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice, which were injected with primary leukemic cells. Purity of PDX cells was enriched to over 90% and presence or absence of JAK2 lesions was validated. PDX and primary leukemic cells were exposed to a dilution series of momelotinib or ruxolitinib for four days. Where indicated, cells were pre-incubated with 25 ng/ml TSLP for 1 hour. In mono-culture assays, cytotoxicity was quantified using MTT and in co-culture assays flow cytometry was used. Leukemic cells were discriminated from mesenchymal stromal cells (MSCs) using CD19 and viability was assessed by Annexin V and Propidium Iodide. Western blotting was used to study protein expression levels. Results JAK2 translocations were detected in 6.5% of BCR-ABL1-like cases (3 PAX5-JAK2 cases, 1 TERF2-JAK2 case and 1 BCR-JAK2 case), but not in B-other cases. JAK2 mutations were identified in 3.5% of all BCP-ALL cases, which included JAK2 mutations in BCR-ABL1-like (7.6%), B-other (11.9%), and high hyperdiploid cases (1.6%), but not in MLL rearranged, BCR-ABL1-positive, ETV6-RUNX1-positive or TCF3-PBX1-positive cases. Cumulative incidence of relapse in patients harboring JAK2 lesions was as poor as in JAK2 wildtype BCR-ABL1-like and B-other patients. Efficacy of the JAK1/2 inhibitors momelotinib and ruxolitinib was examined in JAK2 lesion positive (primary and PDX) leukemic cells. Inhibitors were cytotoxic in both translocated and mutated cells, although efficacy in JAK2 mutated cells highly depended on CRLF2 activation by TSLP. CRLF2 activation resulted in downstream STAT5 activation and sensitization towards ruxolitinib compared to unstimulated cells (p < 0.05). Cells harboring JAK2 translocations signaled independently of CRLF2. Although momelotinib and ruxolitinib exposure blocked downstream STAT1/5 phosphorylation, both inhibitors also induced accumulation of phosphorylated JAK2Y1007. Consequently, release of the inhibitors resulted in a profound re-activation of JAK2 signaling, observed by upregulation of downstream STAT1/5 signaling. Furthermore, we observed microenvironment-induced resistance. Culturing leukemic cells in the presence of primary bone marrow MSCs induced resistance to ruxolitinib, compared to leukemic cells in single cultures (p < 0.05). A similar trend was observed for momelotinib. In addition, patients harboring JAK2 mutations displayed a heterogeneous leukemic cell population. Mouse xenograft models revealed different outgrowth patterns of leukemic cells, in which the JAK2 mutated clone persisted, decreased or even disappeared, resulting in outgrowth of JAK2 wildtype leukemic cells. Moreover, JAK2 mutations were not mutually exclusive for other pathway mutations (e.g. KRAS). Conclusion JAK2 translocations and mutations were detected in poor prognostic BCP-ALL cases. In ex vivo assays, the JAK1/2 inhibitors momelotinib and ruxolitinib were cytotoxic in JAK2 aberrant cells. Despite these promising findings, we identified certain limitations of these inhibitors. Inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon their release. Furthermore, our data suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and by microenvironment-induced resistance. Taken together, our data yield important directives for the clinical use of JAK inhibitors in pediatric BCP-ALL. Disclosures No relevant conflicts of interest to declare.

International audience; In 2006, a remarkable collaboration between University of Texas MD Anderson Cancer Center clinicians andTexas and New Mexico State legislators led to the formation of a dedicated IBC Research Program and Clinicat MD Anderson. This initiative provided funding and infrastructure to foster coordination of an IBC WorldConsortium of national and international experts, and launch the first ever IBC international conference in2008, which brought together experts from around the world to facilitate collaborations and accelerateprogress. Indeed great progress has been made since then. National and international experts in IBCconvened at the 10th Anniversary Conference of the MD Anderson IBC Clinic and Research Program andpresented the most extensive sequencing analysis to date comparing IBC to non-IBC, gene- andprotein-based immunoprofiling of IBC versus non-IBC patients, and converging lines of evidence on thespecific role of the microenvironment in IBC. Novel models, unique metabolic mechanisms, and prominentsurvival pathways have been identified and were presented. Multiple clinical trials based on the work of thelast decade are in progress or in development. The important challenges ahead were discussed. This progressand a coordinated summary of these works are presented herein.

The genetic and epigenetic aberrations that underlie immune resistance lead to tumors that are refractory to clinically established and experimental immunotherapies, including monoclonal antibodies and T cell-based therapies. From various forms of cytotoxic T cells to small molecule inhibitors that revamp the tumor microenvironment, these therapies have demonstrated notable responses in cancer models and a resistant subset of cancer patients, used both alone and in combination. However, even current approaches, such as those targeting checkpoint molecules, tumor ligands, and involving gene-related therapies, present a challenge in non-responding patients. In this perspective, we discuss the most common mechanisms of immune resistance, including tumor heterogeneity, tumor ligand and major histocompatibility complex modulation, anti-apoptotic pathways, checkpoint inhibitory ligands, immunosuppressive cells and factors in the tumor microenvironment, and activation-induced cell death. In addition, we discuss the strategies designed to circumvent these resistance pathways to showcase the potential of emerging technologies in battling the rise of resistance.

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC.

Overcoming resistance to standard anticancer treatments represents a significant challenge. The interest regarding cancer stem cells, a cellular population that has the ability to self-renew and to propagate the tumor, was prompted by experimental evidence delineating the molecular mechanisms that are selectively activated in this cellular subset in order to survive chemotherapy. This has also stimulated combination strategies aimed at rendering cancer stem cells vulnerable to anticancer agents. Moreover, cancer stem cells offer a unique opportunity for modeling human cancers in mice, thus emerging as a powerful tool for testing novel drugs and combinations in a simulation of human disease. These novel animal models may lay the foundation for a new generation of clinical trials aimed at anticipating the benefit to patients of anticancer therapies.

がん進展制御研究所, Mutations in Kirsten rat-sarcoma (KRAS) are well appreciated to be major drivers of human cancers through dysregulation of multiple growth and survival pathways. Similar to many other non-kinase oncogenes and tumor suppressors, efforts to directly target KRAS pharmaceutically have not yet materialized. As a result, there is broad interest in an alternative approach to develop therapies that induce synthetic lethality in cancers with mutant KRAS, therefore exposing the particular vulnerabilities of these cancers. Fueling these efforts is our increased understanding into the biology driving KRAS mutant cancers, in particular the important pathways that mutant KRAS governs to promote survival. In this mini-review, we summarize the latest approaches to treat KRAS mutant cancers and the rationale behind them. © 2014 The Authors.

Certain types of leukemia are amongst the first neoplasias to be “cured” with relatively high 5-year remission rates. This is largely due to targeted therapeutics. However, considerable resistance to tumor-specific targeting drugs has developed due to the presence of abundant cancer stem cells, profound genetic diversity, redundant growth/survival pathways and residual disease. Although these issues propose a challenge, they also provide the opportunity for novel innovations of therapy which currently include the development of multi-target kinase inhibitors, multiple drugs acting on multiple targets, key upstream targets covering multiple downstream targets and the future direction of hybrid molecules targeting two or more targets in different pathways.

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.

Part 1: Multifunctional Agents for Cancer-Imaging and Photodynamic Therapy: Monomers vs. Polyacrylamide-Based Nanoplatforms (Aimee Marko, Nayan J Patel, Penny Joshi, Joseph R Missert and Ravindra K Pandey) Design and Synthesis of Photosensitizers-peptide conjugates for PDT (Turslai M Williams, Martha Sibrian-Vazquez and M Graca H Vicente) Current Devcelopments in Using Meso (tetra) Substituted Porphyrins in PDT (Yasser M Shaker, Ayman M K Sweed, Claire Moylan, Luke Rogers, Aoife A Ryan, Rosine Petitdemange and Mathias O Senge) (Mike Detty et al.) Phthalocyanines in Cancer-Imaging and Therapy (Hasrat Ali and Johan E van Lier) Molecular Phthalocyanines-Based Photosensitizers for Photodynamic Therapy (Pui-Chi Lo, Sun Y S Chow and Dennis K P Ng) Porphyrin Nanoparticles for cancer Imaging and Photodynamic Therapy (Liyang Cui, Juan Chen and Gang Zheng) Photodynamic Therapy Dosimetry: A to Z (Michael S Patterson) Part 2: PDT: Death and Survival Pathways (David Kessel) Vascular Effect of Photodynamic Therapy of Tumors (Keith A Cengel, Charles B Simone and Theresa M Busch) ETNBS in Photodynamic Therapy (Nicholas H Nowell, Hsin-I Hung, Lauren A Austin and Conor L Evans) Negative Impact of Tumor-Generated Nitric Oxide on Photodtynamic Therapy (Albert W Girotti) On the use of Photodynamic Therapy, as Monotherapy or in Combination, in the Treatment of Polypoidal Choroidal Vasculopathy: an Update (Hubert van den bergh and Patrycja Nowak-Sliwinska) Part 3: Photodynamic Therapy of Head and Neck Cancer - What's Old and What's New (Merrill A Biel) Endoscopic Photodynamic Therapy for Advanced Inoperable Esophageal Cancer PDT for Lung Cancer (Keishi Ohtani and Norihiko Ikeda) New Developments in Antimicrobial PDT (Wolfgang Baumler by Joerg Lindenmann)

Gliomas and medulloblastomas are the most frequent malignant brain tumors in adult and children respectively. Although both tumors arise in the CNS, there is a significant difference in their therapeutic response. Medulloblastomas are relatively curable, while glioblastomas are basically incurable. During the last decade several reports have demonstrated the existence of cancer stem cells in brain tumors, their location and their response to treatment. We have recently described the therapeutic response of medulloblastomas to radiation in their native microenvironment, illustrating how p53 and Pi3K signaling pathways lead to the evasion of cell death by the nestin-expressing cells in the perivascular stem cell niche, even while the bulk of tumor succumbs to apoptosis.(1) It remains to be determined whether this mechanism of tumor resistance applies to the more complex stem-cell niche and tumor bulk of gliomas.

Prevention of cancer through dietary intervention recently has received an increasing interest, and dietary polyphenols have become not only important potential chemopreventive, but also therapeutic, natural agents. Polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. They might lead to the modulation of proteins in diverse pathways and require the integration of different signals for the final chemopreventive or therapeutic effect. Polyphenols have been demonstrated to act on multiple key elements in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis and metastasis; however, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of potential chemopreventive and therapeutic activities of dietary polyphenols with emphasis in their ability to control intracellular signalling cascades considered as relevant targets in a cancer preventive approach., S. Ramos has a Ramón y Cajal contract from the Spanish Ministry of Science and Technology. This work was supported by the grants AGL2004-302 from the Spanish Ministry of Science and Technology (CICYT).

Mantle cell lymphoma, characterized by proliferation of mature B lymphocytes, is one of the most aggressive lymphomas. What molecular pathways are involved in its pathogenesis, and how can these be exploited to predict patient prognosis and design new therapies? Mantle cell lymphoma (MCL) is a well-defined lymphoid malignancy characterized by a rapid clinical evolution and poor response to current therapeutic protocols. The genetic and molecular mechanisms involved in its pathogenesis combine the dysregulation of cell proliferation and survival pathways with a high level of chromosome instability that seems related to the disruption of the DNA damage response pathway. Understanding these mechanisms and how they affect tumour behaviour is providing the rationale for the identification of reliable predictors of clinical evolution and the design of innovative therapeutic strategies that could open new avenues for the treatment of patients with MCL.

Mantle cell lymphoma (MCL) remains one of the more challenging sub-types of non-Hodgkin lymphoma. This entity, which is only approximately 10 years old, is characterized by response to many different chemotherapy regimens, though the duration of those responses remains often times quite short. Retreatment with second and third line combination regimens results in shorter and shorter durations of response, with the rapid emergence of a very drug-resistant phenotype. Despite these often frustrating clinical features, there is now a lot of new hope in managing patients with MCL. New insights into the molecular pathogenesis of MCL has revealed a plethora of new potential targets, while our continued efforts in novel targeted drug development has produced a host of agents that are already helping patients with this challenging disease. The use of proteasome inhibitors, for example, represents one example of a new strategy that has offered new hope for patients, and new opportunities for the physician treating this disease. In this review, we will put this biology into perspective, and describe how new revelations in MCL pathogenesis are leading to the identification of many exciting new drugs with promising activity.

Despite the last decade’s improvements in the development of new treatments, mortality of cancer patients is still highly linked to chemoresistance and further occurrence of distant metastasis. The metastatic dissemination is a complex process composed of different steps in which only tumor cells with the highest capacity of adaptation will succeed in establishing and growing at distant sites. Through genetic mutations those cells acquire the chemoresistance features needed to survive in new environments. Nowadays, breast and prostate cancer patients have a risk of being bad responders to chemotherapeutic drugs and to consequently relapse through the development of bone metastasis. Indeed, bone is the most attractive niche for the homing of those cancer cell types. MicroRNAs (miRNAs), a class of small non-coding single strand RNAs, have been recognized as crucial regulatory factors implicated in various cellular processes including cancer initiation and spreading. As miRNAs intensively regulate mediators of migratory and survival pathways, it’s now well established that this class of molecules consequently influences both metastatic dissemination and chemoresistance. Here, we aim to overview the recent research progress on the role of dissemination and chemoresistance-related miRNAs, in the bone-associated tumor context. These pieces of evidence support the clinical use of miRNAs as diagnosis and prognosis markers, as well as potential therapeutic tools against cancer progression, resistance, recurrence and metastatic dissemination.

The ability of a tumor cell population to grow exponentially represents an imbalance between cellular proliferation and cellular attrition. There is an overwhelming body of evidence suggesting the ability of tumor cells to avoid programmed cellular attrition, or apoptosis, is a major molecular force driving the progression of human tumors. Apoptotic evasion represents one of the true hallmarks of cancer and appears to be a vital component in the immunogenic, chemotherapeutic, and radiotherapeutic resistance that characterizes the most aggressive of human cancers [Hanahan and Weinberg, 2000]. The challenges in the development of effective treatment modalities for advanced prostate cancer represent a classic paradigm of the functional significance of anti-apoptotic pathways in the development of therapeutic resistance.

Defects in initiating or executing cell death programs are responsible for cancer chemoresistance. The growing understanding of apoptotic programs suggests that compounds simultaneously inhibiting multiple signaling pathways might provide a better therapeutic outcome than that of individual inhibitors.Natural compounds can modulate different survival pathways, thus enhancing the therapeutic effects of anticancer treatments. This review provides an overview of the preclinical and clinical relevance of chemosensitization, giving special reference to curcumin (CUR) and sulforaphane (SFN) as agents to overcome apoptosis resistance against chemotherapy.Even if CUR and SFN are common dietary constituents, they are characterized by several problems still unresolved and hampering their development as anticancer drugs. For a drug to be safe, it must be devoid of toxicity, and some studies conducted to date raises concern about CUR and SFN safety. Moreover, the efficacy of a drug, alone or in association, is usually determined by randomized, placebo-controlled, double-blind clinical trials. No such trials have shown CUR and SFN to be effective so far. Thus, caution should be exercised when suggesting the use of CUR or SFN for cancer-related therapeutic purpose, especially for very early stage of malignancy, or in patients who are undergoing chemotherapy.

Preterm birth is defined as any delivery before 37 complete weeks of gestation. It is a universal challenge in the field of obstetrics owing to its high rate of mortality, long-term morbidity, associated human suffering and economic burden. In the United States, about 12.18% deliveries in 2009 were preterm, producing an exorbitant cost of $5.8 billion. Infection-associated premature rupture of membranes (PROM) accounts for 40% of extremely preterm births (

Summary: The efficacy of targeted therapies against mutationally activated kinases is typically limited by the engagement of growth-promoting cues that compensate for inhibition of the targeted kinase. Initial studies have highlighted the contribution of genomic alterations, functional characteristics, and signaling feedback loops—all intrinsic to cancer cells—in sustaining such substitute activities. New evidence now indicates that the relative expression of growth factor ligands produced by the tumor microenvironment can relay redundant survival pathways, which may broadly impair responsiveness to kinase inhibitors. Cancer Discov; 2(10); 876–80. ©2012 AACR.

Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. Recent studies have elucidated a key signaling axis, the EGFR-STAT3-Bcl-XL signaling axis, that is aberrantly activated in a majority of HNSCC and contributes to the proliferation and survival of malignant cells. Considerable effort is being placed on developing highly specific inhibitors of different components of this pathway. This review highlights the progress that is being made towards achieving potent inhibition of the EGFR-STAT3-Bcl-XL signaling axis in HNSCC and the promising therapeutic strategies that are currently under development for this disease.

Glioma cells, both within solid tumors and during invasion, exist in surroundings that are subject to a variety of stresses, including metabolic and environmental stresses. Nonetheless, glioma cells survive and can even thrive under hostile conditions, such as hypoxia, nutrient deprivation, and therapeutic regimens. In order to survive, these tumor cells have to find a way to adapt to such an environment by activating certain growth factor and survival pathways while down-regulating cell death mechanisms. In fact, gliomas adapt so well that they not only survive but proliferate by creating a more hospitable environment through new blood vessel formation and dissemination, even as they endure additional stresses along the way. This chapter reviews the basic stresses that glioma cells encounter during the progression of tumor formation and therapeutic interventions.

There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24−/low and/or CD133+ expression) or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), have been demonstrated to have stem/progenitor cell properties, and are tumorigenic when injected in immunocompromized mice at very low concentrations. BCIC have also been isolated and in vitro propagated as non-adherent spheres of undifferentiated cells, and stem cell patterns have been recognized even in cancer cell lines. Recent findings indicate that aberrant regulation of self renewal is central to cancer stem cell biology. Alterations in genes involved in self-renewal pathways, such as Wnt, Notch, sonic hedgehog, PTEN and BMI, proved to play a role in breast cancer progression. Hence, targeting key elements mediating the self renewal of BCIC represents an attractive option, with a solid rationale, clearly identifiable molecular targets, and adequate knowledge of the involved pathways. Possible concerns are related to the poor knowledge of tolerance and efficacy of inhibiting self-renewal mechanisms, because the latter are key pathways for a variety of biological functions and it is unknown whether their interference would kill BCIC or simply temporarily stop them. Thus, efforts to develop BCIC-targeted therapies should not only be focused on interfering on self-renewal, but could seek to identify additional molecular targets, like those involved in regulating EMT-related pathways, in reversing the MDR phenotype, in inducing differentiation and controlling cell survival pathways.

I. Abstract Activation of the mammalian target of rapamycin complex 1 (mTORC1) has been observed in many human tumors and mTORC1 inhibitors have been approved for the treatment of renal cell carcinoma and other malignancies. The tuberous sclerosis complex (TSC) proteins directly regulate Rheb, a direct activator of TORC1. Therefore, TSC and the related disease, pulmonary lymphangioleiomyomatosis (LAM) have the most direct biochemical link to mTORC1 dysregulation of any known human disease or syndrome, providing a unique window through which the direct impact of mTORC1 activation in humans can be viewed. Yet, despite the direct links between TSC and mTORC1, the relationship between mTORC1 activation and the unusual clinical manifestations of TSC remains largely mysterious. Furthermore, TORC1 inhibition has only a partial impact on tumors in TSC patients, with regrowth following discontinuation. In this chapter, we will review the evidence of mTORC1 activation in LAM and TSC, discuss the impact of mTORC1 inhibition in mouse models of TSC and consider how these preclinical models can guide the interpretation of the clinical studies of mTORC1 inhibitors in humans with TSC and LAM. We will also consider the growing evidence that at least some of the clinical manifestations of TSC may reflect TORC1-indepenent functions of the TSC proteins. Finally, we will discuss future clinical perspectives for TSC and LAM patients, focusing on therapeutic approaches combining mTORC1 inhibitors and agents targeting survival pathways and/or TSC-dependent/mTORC1-independent pathways.

In response to stress, cells can not only activate survival pathways, but also death pathways, when the stresses are ungovernable. The case of proteasome impairment is emblematic in this respect. Autophagy is induced, as a prosurvival response, which antagonizes apoptosis. As an additional option, cells can activate necrosis. We have found that certain inhibitors of the ubiquitin-proteasome system can activate a rather peculiar type of necrotic death.

Impaired molecular regulation of active (programmed) cell death is one of the most important hallmark of cancer. Apoptosis is the best characterized biochemical and morphological form of cell death, although other forms also exist. Positive regulators of apoptosis are often lost or inactivated, while inhibitor proteins of apoptosis are often upregulated in cancer. Individual variabilities in these molecular strategies contribute to the differences in sensitivity to current anti-cancer therapies and also provide new existing molecular targets for future therapeutic approaches.

The last decade has seen rapid evolution in the management of multiple myetoma. Cytogenetic, molecular, and proteomic techniques have led to a better understanding of the pathophysiology and prognostic markers of this heterogeneous malignancy. New immunomodulatory drugs, such as lenalidomide, which interrupt myetoma growth and survival. pathways have entered into clinical usage. Combined with dexamethasone, oral lenalidomide has proved to be highly effective in patients whose disease has become resistant to conventional therapy. Currently, several. clinical trials are ongoing in order to define the optimal. use of this new agent and its combinations across the spectrum of patients with myetoma. Whether the ultimate outcome of future research wilt be a single-treatment solution for all patients, or whether treatments will become better-tailored to the individual (based on prognostic markers and preexisting co-morbidities) has yet to be determined. (c) 2007 Elsevier Ltd. All rights reserved.

The treatment of Hodgkin lymphoma continues to be based on combination chemotherapy and radiation therapy. Although this treatment strategy produces a high cure rate, short- and long-term toxic effects continue to be problematic for young cured patients. In this review we focus on emerging novel therapies using small molecules that target specific survival pathways in the cancer cells. This approach is aimed at improving the cure rate while reducing treatment-related toxicity.

It is a current idea that carcinogenesis as well as tumor progression are dynamic processes, which involve inherited as well as somatic mutations and include a continuing adaptation to different microenvironmental conditions. There is, in fact, rising evidence that tumor cells are under a persistent stress and that autocrine as well as microenvironment-derived survival factors play a substantial role for the final outcome of the tumor development as well as for response to the anti-tumor therapy. We will review current achievements on the molecular biology of the microenvironment-derived survival signaling and therapeutical approaches, which are presently under clinical development. By the use of plasma cell disorders as an outstanding clinical model, we will discuss the development of novel in vivo preclinical models which recapitulate the human bone marrow milieu. Finally, we will discuss several topics which appear to be relevant for a successful clinical translation of preclinical research in this specific field.

Interferon alpha (IFN-alpha) has been widely used in the treatment of human solid and haematologic malignancies. Although the antitumour activity of IFN-alpha is well recognised at present, no major advances have been achieved in the last few years. Recent findings have provided new information on the molecular mechanisms of the antitumour activity of the cytokine. In fact, IFN-alpha appears to block cell proliferation, at least in part, through the induction of apoptotic effects. This cytokine can also regulate the progression of tumour cells through the different phases of the cell cycle inducing an increase of the expression of the cyclin-dependent kinase inhibitors p21 and p27. However, it must be considered that IFN-alpha is a physiologic molecule with ubiquitously expressed receptors that is likely to activate survival mechanisms in the cell. We have recently identified an epidermal growth factor (EGF) Ras-dependent protective response to the apoptosis induced by IFN-alpha in epidermoid cancer cells. The identification of tissue- and/or tumour-specific survival pathways and their selective targeting might provide a new approach to improve the efficacy of IFN-alpha-based treatment of human cancer. Moreover, new pegylated species of IFN-alpha are now available with a more favourable pharmacokinetic profile. We will review these achievements, and we will specifically address the topic of IFN-alpha-based molecularly targeted combinatory antitumour approaches.