Resistance to the HER2-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-overexpressing metastatic breast cancer. Increased expression or signaling of the insulin-like growth factor-I receptor (IGF-IR) has been reported in a subset of cell lines and clinical samples derived from trastuzumab-resistant breast cancers. Genetic and pharmacologic inhibition of IGF-IR signaling has been shown to improve response to trastuzumab in trastuzumab-na&#xef;ve and trastuzumab-resistant models. In this paper, we will discuss the role of IGF-IR signaling in trastuzumab resistance. Further, we will discuss cotargeting IGF-IR and HER2 as a potential therapeutic strategy for HER2-over-expressing breast cancers that have progressed on trastuzumab treatment.

Rita Nahta

Deciphering the Role of Insulin-Like Growth Factor-I Receptor in Trastuzumab Resistance

Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR). Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR). Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR). The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR).

Georges Said

Marie Guilbert

Hamid Morjani

Roselyne Garnotel

Pierre Jeannesson

Hassan El Btaouri

Extracellular Matrix Proteins Modulate Antimigratory and Apoptotic Effects of Doxorubicin

There have been significant developments in colon cancer research over the last few years, enabling us to better characterize tumors individually and classifying them according to certain molecular or genetic features. Currently, we are able to use KRAS mutational status as a guide to therapy with anti-epidermal growth factor receptor antibodies. Other molecular features under research include BRAF mutation, microsatellite instability, and CpG island methylation. These three molecular features are often associated with tumors that have overlapping phenotypes and can be present simultaneously in the same tumor. However, they carry different prognostic and predictive qualities, making analysis of their interaction relatively complex. Much research thus far has examined the clinical relevance of microsatellite instability in helping determine prognosis and the predictive value of adjuvant 5-fluorouracil chemotherapy in stages II and III colon cancers. BRAF mutation appears to be a biomarker for poor prognosis. CpG island methylation is tightly associated with microsatellite instable tumors and BRAF mutation, but its clinical utility remains uncertain. Hereby, we examine preclinical and clinical data that supports the utilization of all three phenotypes in future research applied to clinical practice.

Christina Wu

Tanios Bekaii-Saab

CpG Island Methylation, Microsatellite Instability, and BRAF Mutations and Their Clinical Application in the Treatment of Colon Cancer

Cancer resistance to therapy presents an ongoing and unsolved obstacle, which has clear impact on patient's survival. In order to address this problem, novel in vitro models have been established and are currently developed that enable data generation in a more physiological context. For example, extracellular-matrix- (ECM-) based scaffolds lead to the identification of integrins and integrin-associated signaling molecules as key promoters of cancer cell resistance to radio- and chemotherapy as well as modern molecular agents. In this paper, we discuss the dynamic nature of the interplay between ECM, integrins, cytoskeleton, nuclear matrix, and chromatin organization and how this affects the response of tumor cells to various kinds of cytotoxic anticancer agents.

Katja Storch

Nils Cordes

Focal Adhesion-Chromatin Linkage Controls Tumor Cell Resistance to Radio- and Chemotherapy

There have been many exciting new breakthroughs in understanding tumour biology. This has opened up the possibility of personalized treatment for people with certain tumours. The epidermal growth factor receptor (EGFR) and K-ras are two such targets that can help classify tumours on a molecular basis and guide treatment decisions. However, there are still questions about how best to implement new molecular tests like these to characterize tumours in clinical practice. Potential obstacles include availability of good quality tissue specimens, access to the right test, and consensus about interpretation, funding, and availability. In this paper, we review these issues, by discussing these two examples in detail and suggest some actions for addressing potential barriers.

Linda Mileshkin

Bhaumik Shah

Michael Michael

Predictive Molecular Tumour Testing: What Are the Obstacles between Bench and Bedside?

Resistance to apoptosis and chemotherapy is a hallmark of cancer cells, and it is a critical factor in cancer recurrence and patient relapse. Extracellular matrix (ECM) via its receptors, the integrins, has emerged as a major pathway contributing to cancer cell survival and resistance to chemotherapy. Several studies over the last decade have demonstrated that ECM/integrin signaling provides a survival advantage to various cancer cell types against numerous chemotherapeutic drugs and against antibody therapy. In this paper, we will discuss the major findings on how ECM/integrin signaling protects tumor cells from drug-induced apoptosis. We will also discuss the potential role of ECM in malignant T-cell survival and in cancer stem cell resistance. Understanding how integrins and their signaling partners promote tumor cell survival and chemoresistance will likely lead to the development of new therapeutic strategies and agents for cancer treatment.

Fawzi Aoudjit

Kristiina Vuori

Integrin Signaling in Cancer Cell Survival and Chemoresistance

Purpose. Bone loss is a common phenomenon following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The study aimed on tolerance and efficacy of zoledronic acid (ZA) in patients after allo-HSCT. Methods. 40 patients&#x02019; with osteoporosis or osteopenia were recruited on this phase II study. ZA was given at a dose of 4&#x02009;mg IV every 3 months for 2 years (yrs). BMD was determined by dual-energy X-ray absorptiometry (LS lumbar spine, FH femur hip). Patients were evaluated for deoxypyridinoline (Dpd) and calcium excretion by longitudinal measurements. Results. 36 patients who had received at least 3 doses of ZA were evaluable. 26 patients had at least two BMD measurements since baseline (BMD group). Among these patients, BMD increased from <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>0.97</mml:mn><mml:mo>&#x000b1;</mml:mo><mml:mn>0.15</mml:mn></mml:math> to <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>1.10</mml:mn><mml:mo>&#x000b1;</mml:mo><mml:mn>0.18</mml:mn></mml:math>&#x02009;g/cm&#x000b2; (LS baseline&#x02014;2&#x02009;yrs, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>&#x00394;</mml:mo><mml:mo>+</mml:mo><mml:mn>11.6</mml:mn><mml:mo>&#x000b1;</mml:mo><mml:mn>6.0</mml:mn></mml:math>%, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>P</mml:mi><mml:mo>&#x0003c;</mml:mo><mml:mn>0.001</mml:mn></mml:math>) and from <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>0.82</mml:mn><mml:mo>&#x000b1;</mml:mo><mml:mn>0.10</mml:mn></mml:math> to <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>0.91</mml:mn><mml:mo>&#x000b1;</mml:mo><mml:mn>0.10</mml:mn></mml:math>&#x02009;g/cm&#x000b2; (FH baseline&#x02014;2&#x02009;yrs, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>&#x00394;</mml:mo><mml:mo>+</mml:mo><mml:mn>7.5</mml:mn><mml:mo>&#x000b1;</mml:mo><mml:mn>7.0</mml:mn></mml:math>%, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>P</mml:mi><mml:mo>&#x0003c;</mml:mo><mml:mn>0.001</mml:mn></mml:math>). Factors associated with an increase in BMD were younger age, female donor sex, and immunosuppression with CSA/MTX. Conclusion. ZA was generally well tolerated; it increases BMD and reduces Dpd excretion significantly in patients with bone loss after allo-HSCT.

Andreas Hausmann

Wolfgang Hill

Hans Joachim Stemmler

Georg Ledderose

Andrea Baur-Melnyk

Susanne Fritsch

Johanna Ullmann

Hans-Jochem Kolb

Sandra Geiger

Johanna Tischer

Bone Loss after Allogeneic Haematopoietic Stem Cell Transplantation: A Pilot Study on the Use of Zoledronic Acid

Objective. Chemotherapy-associated peripheral neuropathy (CAPN) is a painful side-effect of chemotherapy. This study assesses healthcare and workloss costs of CAPN patients with breast, ovarian, head/neck, or non-small cell lung cancer (NSCLC) from a third-party payor/employer perspective. Research Design and Methods. Patients with qualifying tumors, and claims for chemotherapy and services indicative of peripheral neuropathy (PN) within 9-months of chemotherapy (cases) were identified in a administrative claims database. Cases were matched 1&#x2009;:&#x2009;1 to controls with no PN-related claims based on demographics, diabetes history and propensity for having a diagnosis of PN during the study period (based on resource use and comorbidities in a 3-month baseline period). Average all-cause healthcare costs, resource use and workloss burden were determined. Results. Average healthcare costs were &#x24;17,344 higher for CAPN cases than their non-CAPN controls, with outpatient costs being the highest component (with cases having excess costs of &#x24;8,092). On average, each CAPN case had 12 more outpatient visits than controls, and spent more days in the hospital. Workloss burden was higher for cases but not statistically different from controls. Conclusion. This study establishes that breast, ovarian, head/neck, or NSCLC patients with CAPN have significant excess healthcare costs and resource use.

Crystal T. Pike

Howard G. Birnbaum

Catherine E. Muehlenbein

Gerhardt M. Pohl

Ronald B. Natale

Healthcare Costs and Workloss Burden of Patients with Chemotherapy-Associated Peripheral Neuropathy in Breast, Ovarian, Head and Neck, and Nonsmall Cell Lung Cancer

The aim of this study was to establish the criteria for methodology of cellular “anti-IGF-I” therapy of malignant tumours and particularly for glioblastoma multiforme. The treatment of primary glioblastoma patients using surgery, radiotherapy, and chemotherapy was followed by subcutaneous injection of autologous cancer cells transfected by IGF-I antisense/triple helix expression vectors. The prepared cell “vaccines” should it be in the case of glioblastomas or other tumours, have shown a change of phenotype, the absence of IGF-I protein, and expression of MHC-I and B7. The peripheral blood lymphocytes, PBL cells, removed after each of two successive vaccinations, have demonstrated for all the types of tumour tested an increasing level of CD8+ and CD8+28+ molecules and a switch from CD8+11b+ to CD8+11. All cancer patients were supervised for up to 19 months, the period corresponding to minimum survival of glioblastoma patients. The obtained results have permitted to specify the common criteria for “anti-IGF-I” strategy: characteristics sine qua non of injected “vaccines” (cloned cells IGF-I(−) and MHC-I(+)) and of PBL cells (CD8+ increased level).

Jerzy Trojan

Yuexin X. Pan

Ming X. Wei

Adama Ly

Alexander Shevelev

Maciej Bierwagen

Marie-Yvonne Ardourel

Ladislas A. Trojan

Alvaro Alvarez

Christian Andres

Maria C. Noguera

Ignacio Briceno

Beatriz H. Aristizabal

Heliodor Kasprzak

Huynh T. Duc

Donald  D. Anthony

Methodology for Anti-Gene Anti-IGF-I Therapy of Malignant Tumours

Glioblastoma multiforme (GBM) is a commonly occurring brain tumor with a poor prognosis. GBM can develop both &#x201c;de novo&#x201d; or evolve from a previous astrocytoma and is characterized by high proliferation and infiltration into the surrounding tissue. Following treatment (surgery, radiotherapy, and chemotherapy), tumors often reappear. Glioma-initiating cells (GICs) have been identified in GBM and are thought to be responsible for tumors initiation, their continued growth, and recurrence. 
&#x3b2;-catenin, a component of the cell-cell adhesion complex and of the canonical Wnt pathway, regulates proliferation, adhesion, and migration in different cell types. &#x3b2;-catenin and components of the Wnt canonical pathway are commonly overexpressed in GBM. Here, we review previous work on the role of Wnt/&#x3b2;-catenin signalling in glioma initiation, proliferation, and invasion. Understanding the molecular mechanisms regulating GIC biology and glioma progression may help in identifying novel therapeutic targets for GBM treatment.

Mireia Nager

Deepshikha Bhardwaj

Carles Cant&#237;

Loreta Medina

Pere Nogu&#233;s

Judit Herreros

&#x03B2;-Catenin Signalling in Glioblastoma Multiforme and Glioma-Initiating Cells

About this journal

Journal profile

Meet the editorial board

Editor spotlight

Submit your proposal

Do you think there is an emerging area of research that really needs to be highlighted? Or an existing research area that has been overlooked or would benefit from deeper investigation? Raise the profile of a research area by leading a Special Issue.

Chemotherapy Research and Practice