Nearly three quarters of a million American men who have been treated with prostatectomy and/or radiation therapy are experiencing an increasing prostate-specific antigen (PSA) level, a condition known as biochemical recurrence (BCR). Post localized therapy, some of these men will develop distant metastases with time, but many years may pass before signs of clinical progression appear. While androgen deprivation therapy remains a reasonable option for some men with BCR, deferring androgen ablation or offering non-hormonal therapies may be appropriate in patients where the risk of clinical/metastatic progression and prostate cancer specific death is low. Drug development in this space is a challenge because of the heterogeneous and prolonged natural history of biochemically recurrent prostate cancer, as well as the lack of short-term, validated surrogate endpoints for overall survival. In this setting, where randomized clinical trials have not provided definitive evidence of improvements in overall survival, a risk-stratified approach, informed by the patient’s PSA kinetics, comorbidities and personal preferences, is recommended to determine the best management approach.
Rising prostate specific antigen; prostate cancer; hormonal therapy; androgen deprivation therapy; biochemical recurrence
Maintaining bone health is important in all stages of the management of men with prostate cancer. Patients receiving androgen-deprivation therapy (ADT) are at increased risk of treatment-related osteoporosis and patients with bone metastases are at increased risk of skeletal morbidity related to debilitating skeletal-related events (SREs). Osteoclast-targeted agents have a beneficial impact on bone health in patients with prostate cancer. For patients on ADT at high-risk for fracture, bisphosphonates have been shown to increase bone mineral density (BMD), a surrogate for fracture risk, whereas denosumab (Prolia) has been shown to decrease the risk of osteoporotic fractures, in addition to increasing BMD. For patients with castration-resistant prostate cancer (CRPC) with bone metastases, both zoledronic acid (Zometa) and denosumab (Xgeva) have shown benefit in decreasing the rate of SREs. Currently, no agent is approved for the prevention of bone metastases in high-risk patients. Novel systemic agents including radium-223 (Alpharadin), abiraterone (Zytiga), and enzalutamide (Xtandi) have shown a beneficial effect on the rate of SREs in patients with CRPC with bone metastases by directly impacting tumor growth. Integration of these anti-cancer agents with currently approved osteoclast-targeted agents warrants further investigation.
Prostate cancer; Androgen deprivation therapy; Osteoporosis; Bone metastases; Skeletal related events; Bisphosphonate; Zoledronic acid; Denosumab
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Prior to the advent of tyrosine kinase inhibitors like imatinib, there were few treatment options available to patients with metastatic GIST. Surgery was the mainstay of treatment and the prognosis for patients with metastatic GIST was dismal. With the advent of imatinib the prognosis of metastatic GIST has improved dramatically. Second line tyrosine kinase inhibitors (TKI) such as sunitinib and regorafenib have further bettered prognosis, however there is still a need for therapies for patients with disease refractory to TKI therapy. Newer agents such as the Hsp90 inhibitors, PI3K-AKT-mTOR inhibitors and IGF1-R inhibitors are currently under investigation and may have promise. This review discusses the current standard of care in terms of pharmacotherapy, both standard and investigational (summarized in Box 1), in the management of metastatic GIST.
GIST; tyrosine kinase inhibitors; SDH deficient GIST; KIT; PDGFRA; IGF-1R; HSP90
Renal cell carcinoma (RCC) encompasses a heterogeneous group of histological subtypes of which clear-cell RCC (CCRCC) is the most common comprising more than 70–80% of all cases. Papillary renal cell carcinoma (PRCC) is the next most common comprising 10–15% of cases. PRCC is refractory to chemotherapy, immunotherapy and hormonal therapy.
Insights into the biology of clear-cell RCC have identified multiple pathways associated with the pathogenesis and progression of this cancer. This has led to the development of multiple agents targeting these pathways including the small molecule tyrosine kinase inhibitors sorafenib, sunitinib and pazopanib, the monoclonal antibody bevacizumab and the mTOR inhibitors temsirolimus and everolimus. These drugs have shown significant clinical benefits in randomised trials in advanced CCRCC and have become the standard of care for most patients. With the exception of temsirolimus, phase III trials tested these agents in patients with clear-cell histology, and therefore, their efficacy in non-clear cell RCC is unclear. To date, there is no established effective therapy for patients with advanced non-clear cell RCC (NCCRCC). This review will focus on the treatment options of metastatic NCCRCC.
non-clear cell renal cell carcinoma; VEGF; mTOR; targeted therapy; papillary; chromophobe; unclassified; renal medullary carcinoma; collecting duct carcinoma; sarcomatoid dedifferentiation
Hemoglobinopathy; Thalassemia; Sickle cell disease; Gene therapy
Erythrocytes must regulate hemoglobin synthesis to limit the toxicities of unstable free globin chain subunits. This is particularly relevant in β-thalassemia, where β globin deficiency causes accumulation of free α globin, which forms intracellular precipitates that destroy erythroid precursors. Experimental evidence accumulated over more than 40 years indicates that erythroid cells can neutralize moderate amounts of free α globin through generalized protein quality control mechanisms including molecular chaperones, the ubiquitin proteasome system and autophagy. In many ways, β-thalassemia resembles protein aggregation disorders of nervous system, liver and other tissues, which occur when levels of unstable proteins exceed cellular compensatory mechanisms. It is likely that information gained through studies of non-erythroid protein aggregation disorders can be exploited to further understand and perhaps treat β-thalassemia.
hemoglobin; thalassemia; protein quality control
Triple negative breast cancer (TNBC) defined as lacking expression of the estrogen receptor, progesterone receptor and HER2, comprises approximately 15% of incident breast cancers and is over-represented among those with metastatic disease. It is increasingly clear that TNBC is heterogeneous and that there are several biologically distinct subtypes within TNBC, in particular the basal-like subtype but also the claudin-low, among others. While the incidence of BRCA mutations across all subsets of breast cancer is quite low (~5%), BRCA mutations are more common among those with TNBC (~20%) and may have therapeutic implications. The general principles guiding the use of chemotherapy and radiation therapy do not differ dramatically between early stage TNBC and non-TNBC. There is a trend, however, to treat TNBC at a lower stage with chemotherapy as this is the only way to systemically reduce recurrence risk. In the metastatic setting, while cytotoxic chemotherapy is the mainstay of treatment for advanced TNBC, there are many promising targeted therapies in development in both the preclinical and early phase clinical trial settings. While the treatment of TNBC remains a challenge, coordinated efforts between clinician/scientist partnerships providing a comprehensive understanding of TNBC genomic, proteomic and other biologic processes may result in individualized therapy for TNBC faster than other subtypes -- driven by both the heterogeneity we know exists within this clinical entity and the intense need for improved treatment.
breast cancer; triple negative; chemotherapy; targeted agents; radiation; BRCA mutation
colorectal; lower GI; cancer; genetic syndrome; risk
Acute lymphoblastic leukemia; Philadelphia chromosome; BCR-ABL; tyrosine kinase inhibition; allogeneic stem cell transplant
platelet factor 4; PF4; heparin; PF4/H complexes; HIT
Immune thrombocytopenia (ITP) is a common hematologic disorder characterized by isolated thrombocytopenia. ITP presents as a primary form characterized by isolated thrombocytopenia (platelet count < 100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia, or a secondary form in which immune thrombocytopenia develops in association with another disorder that is usually immune or infectious. ITP may affect individuals of all ages, with peaks during childhood and in the elderly, in whom the age specific incidence of ITP is greatest. Bleeding is the most common clinical manifestation of ITP, with the risk of bleeding and related morbidity increased in elderly patients. The pathogenesis of ITP is complex, involving alterations in humoral and cellular immunity. Thrombocytopenia is caused by antibodies that react with glycoproteins expressed on platelets and megakaryocytes (glycoprotein IIb/IIIa, Ib/IX and others), causing shortened survival of circulating platelets and impairing platelet production. Diminished numbers and function of regulatory T cells, as well as the effects of cytotoxic T cells also contribute to the pathogenesis of ITP. Corticosteroids remain the most common first line therapy for ITP, occasionally in conjunction with intravenous immunoglobulin (IVIg) and anti-Rh(D). However, these agents do not lead to durable remissions in the majority of adults with ITP, and considerable heterogeneity exists in the use of second line approaches, which may include splenectomy, Rituximab, or thrombopoietin receptor agonists (TRAs). This review summarizes the classification and diagnosis of primary and secondary ITP, as well as the pathogenesis and options for treatment. Remarkable advances in the understanding and management of ITP have been achieved over the last decade, though many questions remain.
immune; thrombocytopenia; ITP; platelets; thrombopoietin; splenectomy
Gene profiling; Thrombosis; Hemostasis; Megakaryocytopoiesis; Proteomics
Platelets; Hemostasis; Vascular injury; Signal transduction; Networks; G protein–coupled receptors; G proteins; Integrins
Acute promyelocytic leukemia (APL) is a distinct morphologic variant of acute myeloid leukemia (AML), accounting for approximately 10% to 15% of the adult cases of AML diagnosed in the United States annually.1 The leukemia cells are usually easy to distinguish morphologically from others2 and are characterized by a specific reciprocal translocation t(15;17),3 which fuses the PML (promyelocyte) gene from chromosome 15 to the RAR-α (retinoic acid receptor-α) gene of chromosome 17.4 Consistently found in all cases of t(15;17) APL, the resulting PML-RARα fusion gene on der(15) encodes a chimeric transcript of the 2 DNA-binding domains that shows altered transcriptional regulatory properties, eventually leading to the block of retinoic-acid– induced myeloid differentiation.4
Acute promyelocytic leukemia; All-trans retinoic acid; Arsenic trioxide; Targeted therapies; Cure
Numerous targeted therapies are being developed for patients with CLL. CAR-modified T cells targeting CD19 expressed by normal and malignant B cells is a unique therapy and recent results from four different trials highlight the dramatic potential of this therapy for patients with relapsed CLL. Since adoptive transfer of CAR-modified T cells is a novel approach to cancer therapy there are issues for the medical oncologist to consider when evaluating current and future clinical trials for patients with CLL. Herein, we review the impact of CAR design, T cell production, T cell dose, conditioning regimens, and tumor burden at the time of CAR-modified T cell infusion on the efficacy of this therapy.
Chimeric Antigen Receptor; Chronic Lymphocytic Leukemia; CD19; Adoptive cell therapy; Cell engineering
Phosphoinositide 3’-kinase (PI3K) is a key node in the B cell receptor (BCR) pathway, which plays a crucial role in the trafficking, survival, and proliferation of chronic lymphocytic leukemia (CLL) cells. We review the biology of the PI3K with a focus on its relationship to the CLL microenvironment. We then discuss the biologic rationale underlying the development of PI3K inhibitors in CLL. Delta-isoform specific PI3K inhibitors such as GS1101 (formerly CAL-101) are highly selective for CLL cells and have progressed furthest in their clinical development. Though less specific, pan-PI3K inhibitors and dual PI3K/mTOR inhibitors have the potential to overcome possible resistance mechanisms to isoform-specific inhibition. In early phase clinical trials, PI3K inhibitors appear to be highly active in relapsed refractory CLL, including in high-risk disease such as del(17p). Like other BCR pathway antagonists, they typically induce early transient lymphocytosis with associated nodal response. We examine potential biomarkers for clinical response to PI3K inhibitors such as ZAP-70, IGHV status, and CCL3. We also explore where PI3K inhibition may fit in the evolving landscape of CLL therapy.
Lymphoid Leukemia; Signaling Therapies
This article discusses recent advances in genomic approaches used to understand chronic lymphocytic leukemia (CLL). We describe tools for analyzing DNA sequence level alterations, summarize data obtained from these various platforms, and discuss the clinical relevance of these findings.
CLL; Genomics; CGH; SNP Arrays; Linkage Mapping; GWAS; Whole-exome sequencing; Whole-genome sequencing
Chronic lymphocytic leukemia; Microenvironment; B-cell receptor signaling; Targeted therapy
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