chronic granulomatous disease; gene defects; NADPH oxidase; immune defect; neutropenia
In vivo animal models have proven very useful to understand basic biological pathways of the immune system, a prerequisite for the development of innovate therapies. This manuscript addresses currently available models for defined human monogenetic defects of neutrophil granulocytes, including murine, zebrafish and larger mammalian species. Strengths and weaknesses of each system are summarized, and clinical investigators may thus be inspired to develop further lines of research to improve diagnosis and therapy by use of the appropriate animal model system.
Chronic granulomatous disease; leukocyte adhesion deficiency; severe congenital neutropenia; neutrophils; mouse models; zebrafish models
There are two main forms of hereditary neutropenia: cyclic and severe congenital neutropenia (SCN). Cyclic neutropenia is an autosomal dominant disorder in which neutrophil counts fluctuate between nearly normal levels and close to zero with 21-day periodicity. In contrast, SCN, also known as Kostmann syndrome, consists of chronic and profound neutropenia, with a characteristic promyelocytic maturation arrest in the bone marrow. Unlike cyclic neutropenia, SCN displays frequent acquisition of somatic mutations in the gene, CSF3R, encoding the Granulocyte Colony-Stimulating Factor Receptor (G-CSFR), and a strong predisposition to developing myelodysplasia (MDS) and/or acute myeloid leukemia (AML). Cyclic neutropenia is caused by heterozygous mutations in the gene, ELANE (formerly known as ELA2), encoding the neutrophil granule serine protease, neutrophil elastase. SCN is genetically heterogeneous, but it is most frequently associated with ELANE mutations. While some of the different missense mutations in ELANE exhibit phenotype-genotype correlation, the same mutations are sometimes found in patients with either form of inherited neutropenia. The mutations lead to production of a mutant polypeptide, but no common biochemical abnormality, including effects on proteolysis, has been identified. Two non-mutually exclusive theories have been advanced to explain how the mutations might produce neutropenia. The mislocalization hypothesis states that mutations within neutrophil elastase or involving other proteins responsible for its intracellular trafficking cause neutrophil elastase to accumulate in inappropriate subcellular compartments. The misfolding hypothesis proposes that mutations prevent the protein from properly folding, thereby inducing the stress response pathway within the endoplasmic reticulum (ER). We discuss how the mutations themselves provide clues into pathogenesis, describe supporting and contradictory observations for both theories, and highlight outstanding questions relating to pathophysiology of neutropenia.
Cyclic neutropenia; Severe congenital neutropenia; ELANE; Neutrophil elastase; Granulocyte-colony stimulating factor (G-CSF)
Melanoma is considered a chemotherapy-resistant tumor, but in fact several chemotherapeutic agents show single-agent activity at the level of 10% to 15%, similar to the efficacy of the chemotherapeutic armamentarium used against other tumor types. Several combination chemotherapy regimens have been tested, but no survival benefit has been demonstrated. Few of these trials have been compared with standard dacarbazine (DTIC) in an adequately powered randomized trial, and even the largest of these trials were only powered to detect unrealistically large improvements in overall survival. In this article, the authors review past chemotherapy trials and the current state of chemotherapy for melanoma. Looking to the future, the authors are encouraged by recent observations that the addition of sorafenib to DTIC (or temozolomide) can increase response rates and survival. The authors suggest that this could form the core on which additional active chemotherapeutic drugs could be added with the hope of developing a regimen that improves overall survival. This paradigm of stepwise addition of active chemotherapeutic drugs has been successful in the development of chemotherapy regimens that improve survival in other solid tumor systems. In colon carcinoma, for example, the current regimens were built on fluorouracil (5FU)/leucovorin, which has similar activity to DTIC in melanoma. This could serve as a model for studies on melanoma.
Dacarbazine; Temozolomide; Cisplatin; Sorafenib; Combination chemotherapy
Vasomotor symptoms; Sexual dysfunction; Infertility; Osteoporosis; Musculoskeletal pain; Cognitive changes; Neuropathy; Treatment-related cancers
Immunosuppression; Myelodysplastic syndrome; Tumor necrosis factor; IFNγ
Since the discovery of activating mutations in JAK2 in patients with myeloproliferative neoplasms (MPNs) in 2005, gene discovery efforts have identified additional disease alleles which can predate or occur subsequent to acquisition of JAK2/MPL mutations. In 2009, single nucleotide polymorphism (SNP) arrays and comparative genomic hybridization array (aCGH) based profiling led to the identification of somatic copy-number loss and mutations in the genes TET2 and ASXL1 in MPN patients. Biochemical and biological characterization of the TET and ASXL family of proteins have provided valuable insights into new modes of epigenetic regulation of gene transcription. Mutations in TET2 and ASXL1 are also important biomarkers for disease outcome amongst patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Despite these important insights, the relevance of these mutations to outcome and to therapeutic response in MPN patients is not yet clear. Genetic analysis of MPN patient cohorts with adequate sample size and clear clinical annotation are needed to understand the importance of these mutations on MPN phenotype, risk of transformation to leukemia, response to therapy, and influence on overall survival.
ASXL1; TET2; Myelofibrosis; Myeloproliferative Neoplasms; JAK2
Myeloproliferative neoplasm (MPN) animal models accurately re-capitulate human disease in mice and have been an important tool for the study of MPN biology and therapy. Transplantation of BCR-ABL transduced bone marrow cells into irradiated syngeneic mice established the field of MPN animal modeling and the retroviral bone marrow transplantation (BMT) assay has been used extensively since. Genetically engineered MPN animal models have enabled detailed characterization of the effects of specific MPN associated genetic abnormalities on the hematopoietic stem and progenitor cell (HSPC) compartment and xenograft models have allowed the study of primary human MPN-propagating cells in vivo. All models have facilitated the pre-clinical development of MPN therapies. JAK2V617F, the most common molecular abnormality in BCR-ABL negative MPN, has been extensively studied using retroviral, transgenic, knock-in and xenograft models. MPN animal models have also been used to investigate additional genetic lesions found in human MPN and to evaluate the bone marrow microenvironment in these diseases. Finally, several genetic lesions, although not common, somatically mutated drivers of MPN in humans induce a MPN phenotype in mice. Future uses for MPN animal models will include modeling compound genetic lesions in MPN and studying myelofibrotic transformation.
Myeloproliferative neoplasms; preclinical murine models; BCR-ABL; JAK2V617F; hematopoietic stem cells; bone marrow microenvironment; myelofibrosis; oncogenes
Methotrexate; pralatrexate; pemetrexed; antifolates; reduced folate carrier (RFC); proton-coupled folate transporter (PCFT); folate receptors; folate receptor-mediated endocytosis
The IGF axis is a tightly controlled endocrine system that regulates cell growth and development, known to have an important function in cancer biology. IGF1 and IGF2 can promote cancer growth in a GH-independent manner both through paracrine and autocrine secretion and can also confer resistance to chemotherapy and radiation. Many alterations of this system have been found in neoplasias, including increased expression of ligands and receptors, loss of heterozigosity of the IGF2 locus and increased IGF1R gene copy number. The IGF1 network is an attractive candidate for targeted therapy, including receptor blockade with monoclonal antibodies and small molecule inhibitors of receptor downstream signaling. This article reviews the role of the IGF axis in the initiation and progression of cancer, and describes the recent advances in IGF inhibition as a therapeutic tool.
IGF1R; IGF1; IGF2; insulin; kinase; cancer
‘Driver mutations’ are essential for carcinogenesis as well as tumor progression as they confer a selective growth advantage to cancer cells. Identification of driver mutations in growth related protein kinases, especially tyrosine kinases have led to clinical development of an array of tyrosine kinase inhibitors in various malignancies, including lung cancer. Inhibition of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinases have proven to be of meaningful clinical benefit, while inhibition of several other tyrosine kinases have been of limited clinical benefit, thus far. An improved understanding of tyrosine kinase biology has also led to faster drug development, identification of resistance mechanisms and ways to overcome resistance. In this review, we discuss the clinical data supporting the use and practical aspects of management of patients on epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors.
Non-small cell lung cancer; tyrosine kinase inhibitor; epidermal growth factor receptor; ALK-translocation; Vascular endothelial growth factor
Antibody-based therapeutics against cancer are highly successful in clinic and currently enjoy unprecedented recognition of their potential; 13 monoclonal antibodies (mAbs) have been approved for clinical use in the European Union and in the United States (one, mylotarg, was withdrawn from market in 2010). Three of the mAbs (bevacizumab, rituximab, trastuzumab) are in the top six selling protein therapeutics with sales in 2010 of more than $5 bln each. Hundreds of mAbs including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs and mAbs with optimized pharmacokinetics are in clinical trials. However, challenges remain and it appears that deeper understanding of mechanisms is needed to overcome major problems including resistance to therapy, access to targets, complexity of biological systems and individual variations.
therapeutics; antibodies; cancer; immunogenicity; safety; efficacy
Recently, the development of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors has brought a major breakthrough in the treatment of germline breast cancer susceptibility gene (BRCA)-mutant cancers.1-4 These agents target a DNA repair pathway via a novel mechanism of action. A better understanding of DNA damage repair mechanisms can extend the therapeutic application of this novel drug class to a wide range of sporadic cancers. Early clinical success has accelerated the development of various PARP inhibitors that are being explored in many cancers with single agents or in combination with chemotherapy or radiotherapy. In this article, the authors review DNA repair mechanisms and the role of PARP as a therapeutic target and summarize available PARP inhibitors, their clinical trials, biomarkers of PARP inhibitor sensitivity, and resistance mechanisms.
Poly(ADP-ribose) polymerase; Inhibitor; Synthetic lethality; BRCA
A monoclonal spike (M spike or paraprotein) on serum protein electrophoresis (SPEP) is a frequent finding in the general population and typically is pathognomonic of an asymptomatic, premalignant condition called monoclonal gammopathy of undetermined significance (MGUS). MGUS occurs in around 3% of people older than 50 and is associated with a lifelong, low, yet non negligible, risk of progression to multiple myeloma (MM) or a related plasma cell dyscrasia. It is generally an incidental diagnosis during the evaluation of patients complaining of various symptoms such as fatigue, forgetfulness, or neuropathy. While in most outpatient encounters the paraprotein is non pathogenic and cannot explain the presenting symptoms, both patients and physicians are faced with the medical, psychological and economic consequences of a premalignant diagnosis that is non curable, and the obligation (or lack thereof) for follow up. Lifelong annual medical evaluation and blood testing are currently recommended as a mean to early diagnose progression into asymptomatic (smoldering) or active MM. Recently the foundation of these recommendations have been challenged considering the low rate of progression and potential harm related to over-testing.
As MM remains an incurable disease, a timely diagnosis is crucial to establish an adequate plan of care and potentially prevent significant comorbidities such as pathologic fractures or kidney failure.
In this article we will discuss the criteria for diagnosis of MGUS, smoldering MM (SMM) and symptomatic MM; the risk factors for progression from MGUS and SMM to MM; the current recommendations for follow up of MGUS patients and diagnostic evaluation of suspected MM transformation.
Acute lymphoblastic leukemia; gene mutations, chromosome aberrations; human; prognosis
Kidney neoplasms; mTOR; targeted therapy; renal cell carcinoma; treatment resistance
A majority of adult patients with acute lymphoblastic leukemia (ALL) will die of their disease. While the prognosis for pediatric patients is markedly better, in all cases, the prognosis in patients with relapsed or refractory disease is uniformly poor. Allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor can offer a significant potential therapeutic benefit for some patients. Since most patients lack a suitable related donor, alternative allo-HSCT approaches, including unrelated, umbilical cord blood (UCB), and haploidentical allo-HSCT, have been developed and are increasingly being studied in the clinical setting. Reduced-intensity conditioning further extends access to allo-HSCT for older more comorbid patients. While the use of donor-derived T cell adoptive therapy has a uniformly dismal outcome in patients with relapsed ALL following HSCT, modified adoptive T cell regimens, including the infusion of enriched tumor-targeted donor T cells and genetically targeted T cells, are currently under clinical investigation with promising results. Lastly, natural killer (NK) cells genetically modified to target ALL are also being studied in clinical trials, further expanding therapeutic options for patients with refractory or relapsed ALL. What remains to be seen is whether these novel adoptive cell therapies will ultimately lead to improved clinical outcomes.
Acute lymphoblastic leukemia; adoptive cellular therapy; hematopoietic stem cell transplants; chimeric antigen receptor
CML; imatinib; resistance; BCR-ABL; mutation; hOCT1
Emerging from a largely cytokine-based era, the last several years have witnessed a dramatic change in the therapeutic landscape of renal cancer. Molecularly targeted and antiangiogenic agents now form the backbone of most therapeutic strategies for the majority of patients with advanced renal cell carcinoma (RCC). While the next few years may not see such broad paradigm shifts, there remains significant room for improvement in the care of patients with RCC. In this review, we will discuss challenges which face physicians and researchers going forward as well as innovations which may contribute to improving the therapeutic outcomes for patients with RCC.
Kidney cancer is one of the 10 most common forms of cancer in both men and women. Ninety percent or more of these cancers are believed to be of epithelial cell origin, and are referred to as renal cell carcinoma (RCC). RCCs can be further subdivided, based on their histologic appearance, into clear-cell renal carcinomas (~75%), papillary renal carcinomas (15%), chromophobe tumors (5%), and oncocytomas (5%).1,2 Studies of hereditary kidney cancer families led to the identification of genes that, when mutated in the germline, confer an increased risk of these various histologic RCC subtypes and hence a glimpse at the molecular circuits that are deregulated in these different forms of RCC.2 In practice, there is some overlap among the histologic subtypes (eg, a tumor with predominantly clear-cell features might contain areas more typical of papillary RCC). Similarly, there are some shared molecular features among these tumor types (see later discussion). This review focuses primarily on the most common form of RCC, clear-cell renal carcinoma, while making note of some recent advances in the other histologic subtypes.
Renal cell carcinoma; Clear-cell renal carcinoma; Hypoxia-inducible factor; HIF-responsive gene products
Adoptive immunotherapy; Antiviral therapy; Cytomegalovirus; Hematopoietic stem cell transplantation
Hereditary genodermatoses with cancer predisposition are reviewed, including Nevoid Basal Cell Carcinoma Syndrome, Neurofibromatosis Types 1 and 2, Tuberous Sclerosis Complex, Xeroderma Pigmentosum, and Dyskeratosis Congenita. Hereditary melanoma is also included, though it differs from the others in several respects. The underlying genetic aberrations causing these syndromes are largely known, allowing novel treatments to be developed for some of these disorders. Early recognition and diagnosis allows for close follow-up and surveillance for associated malignancies.
genodermatoses; Nevoid Basal Cell Carcinoma Syndrome; Neurofibromatosis Type 1; Neurofibromatosis Type 2; Tuberous Sclerosis; melanoma; Xeroderma Pigmentosum; Dyskeratosis Congenita