The Protein Kinase D (PKD) family of serine/threonine kinases consists of three members-PKD1, PKD2, and PKD3. While PKD1 in many cancers has been identified as a suppressor of the invasive phenotype, the two other PKD subtypes, PKD2 and PKD3, have been attributed oncogenic functions. In invasive Breast Cancer cells PKD1 expression is downregulated by methylation of the PRKD1 promoter. On the other hand, PKD2 and PKD3 are not silenced, and drive proliferation, invasion, and mediate chemoresistance. Two strategies emerge to utilize this knowledge for novel treatment opportunities. First, pan PKD inhibitors could be developed and used for these aggressive cancers. An alternative approach to obtain similar effects would be to induce the re-expression of PKD1.
Protein Kinase D; PKD; isoforms; breast cancer; therapy
Modern advances in cancer immunotherapy have led to the development of active immunotherapy that utilizes tumor-associated antigens to induce a specific immune response against the tumor. Current methods of immunotherapy implementation are based on the principle that tumor-associated antigens are capable of being processed by antigen-presenting cells and inducing an activated cytotoxic T-lymphocyte-specific immune response that targets the tumor cells. Antigen internalization and processing by antigen-presenting cells, such as dendritic cells, or macrophages results in their surface association with MHC class I molecules, which can be recognized by an antigen-specific cytotoxic T-lymphocyte adaptive immune response. With the aim of augmenting current immunotherapeutic modalities, much effort has been directed towards enhancing antigen-presenting cell activation and optimizing the processing of tumor-associated antigens and major histocompatibility molecules. The goal of these immunotherapy modifications is to ultimately improve the adaptive specific immune response in killing of tumor cells while sparing normal tissues. Immunotherapy has been actively studied and applied in glioblastomas. Preclinical animal models have shown the feasibility of an active immunotherapy approach through the utilization of tumor vaccines, and recently several clinical studies have also been initiated. Recently, endogenous heat-shock proteins have been implicated in the mediation of both the adaptive and innate immune responses. They are now being investigated as a potential modality and adjuvant to immunotherapy, and they represent a promising novel treatment for human glioblastomas.
active immune response; antigen; antigen-presenting cells; cancer vaccines; CTL; heat-shock proteins; immunotherapy; T-cell lymphocytes
Pancreatic cancer, due to its late diagnosis, is difficult to treat. In addition, current therapy options are insufficient and new approaches for combination treatment are required. Recent demonstration of the importance of constitutive signaling of NF-κB-inducing kinase (NIK, also named MAP3K14) in maintaining the high basal activity of the alternative NF-κB pathway in pancreatic cancer suggests novel possibilities for therapeutic intervention. Strategies to target the alternative NF-κB pathway include not only the use of small molecule inhibitors for NIK and IκB kinase α (IKKα), but also broad spectrum approaches such as using proteasome inhibitors or combinatorial approaches targeting both alternative and canonical pathways. These may also act synergistically with currently used drugs.
alternative; MAP3K14; NF-κB; NIK; noncanonical; pancreatic cancer; therapy; TRAF2
In spite of recent advances in molecular diagnostic techniques and expanded indications for allogeneic hematopoietic stem cell transplantation, treatment of acute myeloid leukemia (AML) remains a major challenge. In the last decade, several recurrent genetic abnormalities and gene mutations with prognostic implications have been identified. This has led to improved informed treatment decisions. However, there has been limited change in the use of nonspecific cytotoxic chemotherapy and mortality rates continue to be unacceptably high, with 5 year overall survival rates of older AML patients at 30% or less. Whole-genome sequencing offers hope for greater diagnostic accuracy and is likely to lead to further characterization of disease subsets with differential outcome and response to treatment. The holy grail of personalized targeted therapy for the individual AML patient, while minimizing toxicity and prolonging survival, appears closer than ever.
acute myeloid leukemia; FLT3 mutation; normal karyotype; outcome; PCR; personalized therapy; prognostic factors; treatment; whole-genome sequencing
New agents and treatment strategies that can be safely and effectively integrated into current treatment paradigms for head and neck squamous cell carcinoma (HNSCC) are urgently needed. To date, the anti-EGF receptor (EGFR) monoclonal antibody, cetuximab, is the first and only molecularly targeted therapy to demonstrate a survival benefit for patients with recurrent or metastatic disease. Other anti-EGFR-targeted therapies, including monoclonal antibodies (e.g., panitumumab and zalutumumab) and reversible and irreversible ErbB family tyrosine kinase inhibitors (e.g., lapatinib, afatinib and dacomitinib) are being actively investigated in Phase II and Phase III clinical trials. In addition, validated biomarkers are needed to predict clinical benefit and resistance to anti-EGFR therapy in HNSCC. This review will compare and contrast the mechanisms of action of anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors and also discuss their role in the management of HNSCC and the potential impact of human papillomavirus status in the development of these targeted agents.
epidermal growth factor receptor; head and neck squamous cell carcinoma; HER tyrosine kinase receptor family; therapeutic monoclonal antibody; tyrosine kinase inhibitor
Locoregionally advanced stage III or stage IV cancers; molecular modeling; diagnostic markers; tumor tissue-cancer models; multi-ethnic cohorts; disparities; African American; Caucasian American; human papilloma virus
Advanced urothelial cancer is associated with a poor prognosis and there has been no substantial progress over the past three decades since the development of platinum-based multiagent chemotherapy. Clinical trials evaluating novel agents and combinations including chemotherapeutic drugs, as well as targeted inhibitors, are desperately needed. With a better understanding of the complex molecular alterations that drive urothelial tumorigenesis, new targets for novel therapeutics are being defined. This article will describe the current state of advanced urothelial cancer treatment and provide a comprehensive discussion of novel agents in development.
bladder cancer; targeted therapy; transitional cell carcinoma; urothelial cancer
The American Cancer Society estimates that over 200,000 new breast cancer cases are diagnosed annually in the USA alone. Of these cases, the majority are invasive breast cancers and almost 70% are estrogen receptor-α positive. Therapies targeting the estrogen receptor-α are widely applied and include selective estrogen receptor modulators such as tamoxifen, a selective estrogen receptor downregulator such as Fulvestrant (Faslodex; FAS, ICI 182,780), or one of the third-generation aromatase inhibitors including letrozole or anastrozole. While these treatments reduce breast cancer mortality, many estrogen receptor-α-positive tumors eventually recur, highlighting the clinical significance of endocrine therapy resistance. The signaling leading to endocrine therapy resistance is poorly understood; however, preclinical studies have established an important role for autophagy in the acquired resistance phenotype. Autophagy is a cellular degradation process initiated in response to stress or nutrient deprivation, which attempts to restore metabolic homeostasis through the catabolic lysis of aggregated proteins, unfolded/misfolded proteins or damaged subcellular organelles. The duality of autophagy, which can be either pro-survival or pro-death, is well known. However, in the context of endocrine therapy resistance in breast cancer, the inhibition of autophagy can potentiate resensitization of previously antiestrogen resistant breast cancer cells. In this article, we discuss the complex and occasionally contradictory roles of autophagy in cancer and in resistance to endocrine therapies in breast cancer.
3-methyladenine; antiestrogen resistance; aromatase inhibitor; autophagy; bafilomycin A1; breast cancer; endoplasmic reticulum stress; fulvestrant; hydroxychloroquine; tamoxifen; unfolded protein response
Extensive evidence shows that the active form of vitamin D3 – 1α,25-dihydroxyvitamin D3 – plays an important role in cancer prevention, has tumorostatic activity and may potentially be used in therapy for melanoma. Vitamin D3 and its analogs (secosteroids) exert multiple effects on cancer cells, including inhibition of cell growth and induction of differentiation. Activity of secosteroids depends on multiple cellular factors, including expression of the vitamin D receptor. Despite its endogenous origin, the key drawback for the use of pharmacologically effective doses of 1α,25-dihydroxyvitamin D3 is its hypercalcemic effect leading to profound toxicity. The solution may lie in properties of vitamin D3 analogs with modified side chains, which demonstrate low calcemic activity but conserve the anti-tumor properties. Noncalcemic vitamin D compounds were found to be potent in multiple studies that mandate further clinical testing. Finally, recent studies revealed alternative metabolic pathways for secosteroids and new targets in the cells, which opens up new therapeutic possibilities.
1α,25-dihydroxyvitamin D3; melanoma; secosteroids; VDR; vitamin D; vitamin D analogs; vitamin D receptor
The current standard treatment for muscle-invasive nonmetastatic bladder cancer is neoadjuvant platinum-based chemotherapy followed by radical cystectomy. However, neoadjuvant chemotherapy is not widely accepted even with level 1 evidence. Adjuvant chemotherapy should be discussed if patients have not received neoadjuvant chemotherapy before surgery and have high-risk pathologic features. Although not considered standard of care, bladder-sparing therapy can be considered for highly selected patients and for those medically unfit for surgery. Even though there are no level 1 data, the treatment outcomes for highly select patients given bladder-sparing therapy appear promising, with many patients retaining a functional bladder. Personalized chemotherapy is currently being actively pursued to target the underlying molecular changes and tailor to individual needs.
bladder urothelial carcinoma; chemotherapy; cisplatin; personalized chemotherapy; targeted therapy
Conflicting data and substantial controversy exist regarding optimal adjuvant treatment for those patients with resectable or potentially resectable adenocarcinoma of the pancreas. Despite improvements in short-term surgical outcomes, the use of newer chemotherapeutic agents, development of targeted agents, and more precise delivery of radiation, the 5-year survival rates for early stage patients remains less than 25%. This article critically reviews the existing data for various adjuvant treatment approaches for patients with surgically resectable pancreatic cancer. Our review confirms that despite several randomized clinical trials, the optimal adjuvant treatment approach for these patients remains unclear.
Despite improvements in short-term surgical outcomes, use of newer chemotherapeutic agents, development of targeted agents, and more precise delivery of radiation, the 5-year survival rates for early stage patients remains less than 25%. Despite several randomized clinical trials in these patients, the optimal treatment approach remains unclear. We review data the data regarding adjuvant therapy for patients with early stage pancreas cancer and discuss potential tumor factors that can be used to select patients for optimal adjuvant therapy. The probability of long-term survival is higher in patients who undergo margin-negative resections but local and distant failures are common, indicating the need for adjuvant therapies. Improved systemic treatment is desperately needed and the role of adjuvant radiation remains unclear. Neoadjuvant chemoradiation is being studied as an alternative to postoperative therapy. Potential molecular targets have been identified and the benefit of the addition of biologic agents to adjuvant treatments is being explored.
Pancreatic Adenocarcinoma; Radiotherapy; Combined Modality Therapy; Biological Markers; Molecular Targets; Neoadjuvant
Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.
breast cancer immunity; breast cancer vaccine; clinical trials; immune checkpoint blockade; immune tolerance; immunotherapy; tumor microenvironment
Endometrial cancer (EC) is the most common female genital malignancy in the USA. Most carcinomas arising from the uterus are estrogen dependent and are associated with obesity and hypertension. They are designated type I ECs and typically, due to their early diagnosis secondary to postmenopausal bleeding, have a good prognosis. By contrast, type II ECs develop in older patients, are not hormone dependent and are responsible for most recurrences and deaths from EC. Uterine serous cancer constitutes up to 10% of all endometrial tumors, and represents the most biologically aggressive variant of type II EC. This article will describe the most salient molecular markers that have been identified in uterine serous cancer, thus far with emphasis on the use of erbB2 (HER2/neu) as the first of a series of therapeutic markers for the treatment of this highly-aggressive subset of ECs.
endometrial cancer; erbB2; hRS7; molecular markers; MT-201; patupilone; pertuzumab; targeted therapy; trastuzumab; uterine serous cancer
A major issue relating to many cancers is the absence of effective chemotherapeutic agents; so that most often untreatable morbidity and death are prevalent once the cancer has been detected and has advanced. The search for efficacious anticancer agents is imperative. One potential agent is zinc, which is decreased in the development of some cancers in order to avoid its cytotoxic/tumor suppressor effects on the malignant cells. This provides the basis and opportunity to employ a treatment regimen that restores elevated zinc levels in the malignant cells and elicits the cytotoxic/tumor suppressor effects of zinc. The enigma is that this approach and expectation has not reached fruition. The question is “why?”. This article provides a discussion of relevant zinc issues that need to be considered and resolved. Important areas of research are identified as being essential for the successful application of zinc cytotoxicity/tumor suppression actions for the treatment of specific cancers.
cancer chemotherapy; Clioquinol; prostate cancer; zinc; zinc; ionophore; ZIP transporters
Lung cancer is the leading cause of cancer-related deaths in the Western world. Lungs can be affected by a number of histologically diverse malignancies. Nonetheless, the vast majority of lung cancers are classified as non-small cell lung cancer (NSCLC). Despite extensive research on different therapeutic regimens, the overall 5-year survival of patients diagnosed with NSCLC (all stages) is a dismal 15%. Although strongly correlated with tobacco smoke, there is an increasing NSCLC morbidity in individuals who have never smoked. The pattern of genetic lesions found in NSCLC derived from smokers and never-smokers appears to be different. This fact led to the hypothesis that different, still unidentified carcinogens are responsible for lung cancer onset in never-smokers. All the above considerations compel the scientific community to find novel therapeutic targets to fight such a deadly disease.
In recent years critical pathways governing embryonic development have been increasingly linked to cancer. Here we will focus on the role of Notch signaling in lung cancer. Notch receptors’ activity can be blocked following different strategies, thus representing a promising alternative/complement to the arsenal of therapeutic strategies currently used to treat lung cancer.
lung cancer; cancer progenitor cells; Notch signaling; hypoxia; cancer stem cells; Notch signaling inhibition
Eruptive melanocytic nevi (EMN) is an unusual phenomenon characterized by the abrupt, simultaneous appearance of hundreds of melanocytic nevi on previously uninvolved sun-exposed skin. The mechanisms underlying this phenomenon are not well understood, but have been associated with both systemic immunosuppression and bullous dermatoses. The paper under evaluation brings new insight into the molecular events underlying EMN development in a patient receiving 6-mercaptopurine immunosuppressive therapy for ulcerative colitis. Sequencing of DNA from 20 eruptive nevi revealed the presence of BRAF V600E mutations in 85% of the lesions tested. The role of mutated BRAF in the initiation and progression of melanoma in conjunction with the strong correlation between nevus number and melanoma risk suggests the need for photoprotection in patients receiving thiopurine therapy. The study under evaluation further points to the possible interaction between environmental mutagens and UV radiation in the acquisition of BRAF mutations that may in turn increase the risk of melanoma development.
BRAF; immunosuppression; MAPK; melanoma; nevi; thiopurines; UV
Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of histone acetylation in the modification of chromatin structure and dynamics, and thereby gene transcription regulation, has been well recognized. A steadily growing number of nonhistone proteins have been identified as acetylation targets and reversible lysine acetylation in these proteins plays an important role(s) in the regulation of mRNA stability, protein localization and degradation, and protein–protein and protein–DNA interactions. The recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation, differentiation and apoptosis. Many nonhistone proteins targeted by acetylation are the products of oncogenes or tumor-suppressor genes and are directly involved in tumorigenesis, tumor progression and metastasis. Aberrant activity of HDACs has been documented in several types of cancers and HDAC inhibitors (HDACi) have been employed for therapeutic purposes. Here we review the published literature in this field and provide updated information on the regulation and function of nonhistone protein acetylation. While concentrating on the molecular mechanism and pathways involved in the addition and removal of the acetyl moiety, therapeutic modalities of HDACi are also discussed.
acetylation; cancer therapy; deacetylation; epigenetics; HDAC; HDAC inhibitor; histone deacetylase; nonhistone acetylation
High-dose chemotherapy (HDCT) with autologous stem cell support has been studied in both the salvage and first-line setting in advanced germ cell tumor (GCT) patients with poor-risk features. While early studies reported significant treatment-related mortality, introduction of peripheral blood stem cell transplantation, recombinant growth factors and better supportive care have decreased toxicity; and in more recent reports treatment-related deaths are observed in <3% of patients. Two to three cycles of high-dose carboplatin and etoposide is the standard backbone for HDCT, given with or without additional agents including ifosfamide, cyclophosphamide and paclitaxel. Three large randomized Phase III trials have failed to show a benefit of HDCT over conventional-dose chemotherapy (CDCT) in the first-line treatment of patients with intermediate- or poor-risk advanced GCT, and to date the routine use of HDCT has been reserved for the salvage setting. Several prognostic models have been developed to help predict outcome of salvage HDCT, the most recent of which applies to both CDCT and HDCT in the initial salvage setting. Patients that relapse after HDCT are usually considered incurable, and additional therapy is provided with palliative intent.
chemotherapy; germ cell tumors; high-dose chemotherapy; stem cell transplantation; testicular cancer
HER2 amplification is seen in up to 20% of breast cancers and is associated with an aggressive phenotype. Trastuzumab, a monoclonal antibody to HER2, accrues significant clinical benefit in the metastatic and adjuvant settings. However, some patients suffer disease recurrence despite adjuvant trastuzumab therapy, and many patients with metastatic disease do not respond to therapy or develop refractory disease within 1 year of treatment. Given the increased recognition of de novo and acquired resistance to therapy, considerable research has been dedicated to understanding the molecular mechanisms of trastuzumab resistance. Here, we highlight putative models of resistance, including activation of the downstream PI3K-signaling pathway, accumulation of a constitutively active form of HER2, and crosstalk of HER2 with other growth factor receptors. The identification of these specific mechanisms of trastuzumab resistance has provided a rationale for the development of several novel HER2-targeted agents as the mechanisms have largely suggested a continued tumor dependence on HER2 signaling. We explore the emerging data for the treatment of trastuzumab-refractory disease with novel agents including lapatinib, neratinib, pertuzumab, trastuzumab-DM1, HSP90 and PI3K pathway inhibitors, and the future potential for these inhibitors which, if combined with reliable biomarkers of resistance, may ultimately usher in a new era of personalized medicine for this disease.
17-AAG; breast cancer; HER2; lapatinib; p95-HER2; pertuzumab; resistance; targeted therapy; trastuzumab
Despite being a common cancer worldwide, management of transitional cell carcinoma of the bladder currently relies primarily on clinical staging and histopathologic parameters. Assaying alterations in molecular pathways can contribute valuable information that can accurately predict outcome and chemotherapeutic response in individual patients with bladder cancer. Medium- to high-throughput gene-expression profiling technologies are now allowing multiplexed assessment of alterations responsible for the genesis and progression of bladder tumors. These investigations employ global or pathway-based approaches to define molecular signatures that can predict prognosis independent of traditional clinical performance metrics. Prognostic panels generated using these strategies can also elucidate the biology of tumor progression and identify potential therapeutic targets.
gene-expression profiling; global approach; microarray; multimarker analysis; pathway-specific approach; urothelial carcinoma
Photodynamic therapy (PDT) is a noninvasive procedure that involves a photosensitizing drug and its subsequent activation by light to produce reactive oxygen species that specifically destroy target cells. Recently, PDT has been widely used in treating non-melanoma skin malignancies, the most common cancer in the USA, with superior cosmetic outcomes compared with conventional therapies. The topical ‘photosensitizers’ commonly used are 5-aminolevulinic acid (ALA) and its esterified derivative methyl 5-aminolevulinate, which are precursors of the endogenous photosensitizer protoporphyrin IX. After treatment with ALA or methyl 5-aminolevulinate, protoporphyrin IX preferentially accumulates in the lesion area of various skin diseases, which allows not only PDT treatment but also fluorescence diagnosis with ALA-induced porphyrins. Susceptible lesions include various forms of non-melanoma skin cancer such as actinic keratosis, basal cell carcinoma and squamous cell carcinoma. The most recent and promising developments in PDT include the discovery of new photosensitizers, the exploitation of new drug delivery systems and the combination of other modalities, which will all contribute to increasing PDT therapeutic efficacy and improving outcome. This article summarizes the main principles of PDT and its current clinical use in the management of non-melanoma skin cancers, as well as recent developments and possible future research directions.
5-aminolevulinic acid; ALA; MAL; methyl 5-aminolevulinate; PDT; photodynamic therapy; photosensitizers; skin cancer; topical PDT
The incidence of melanoma is continuing to increase worldwide. UV exposure is a known risk factor for melanoma. Geographic location is known to influence UV exposure and the distribution of the incidence of melanoma. Furthermore, epidemiologic data suggest that gender and genetics may influence the distribution of melanoma on the body surface and histopathologic characteristics of the lesion. This article describes what is known about the impact of gender, ethnicity and geography on the progression of melanoma. Advanced-stage cutaneous melanoma has a median survival time of less than 1 year. Surgical removal, radiotherapy, chemotherapy, targeted therapies and a variety of immunotherapies have been utilized in the treatment of melanoma. Current treatment strategies and the results of recent clinical trials are also discussed in this article.
anatomic distribution; epidemiology; ethnicity; gender; geography; melanoma
Breast cancer is the second leading cause of cancer deaths and is the most frequently diagnosed cancer in women of industrialized nations. Breast cancer progression is a multistep process involving genetic and epigenetic alterations that drive normal breast cells into highly malignant derivatives with metastatic potential. MYC is a proto-oncogene whose protein product contains a basic helix-loop-helix domain. MYC functions as a transcription factor regulating up to 15% of all human genes. MYC is regulated at multiple levels, and the protein is a downstream effector of several signaling pathways. In breast cancer cells, MYC target genes are involved in cell growth, transformation, angiogenesis and cell-cycle control. BRCA1 is linked to transcriptional regulation through interaction with MYC. Although the relationship between amplification and overexpression is not clearly delineated, MYC amplification is significantly correlated with aggressive tumor phenotypes and poor clinical outcomes. MYC amplification is emerging as an important predictor of response to HER2-targeted therapies and its role in BRCA1-associated breast cancer makes it an important target in basal-like/triple-negative breast cancers.
BRCA1; breast cancer; clinical trial; MYC; targeted therapy; transcription regulation; tumor progression
The essence and origin of malignant fibrous histiocytoma (MFH) have been debated for now close to five decades. Originally characterized as a morphologically unique soft tissue sarcoma subtype in 1963 of unclear etiology with a following decade and a half of research only to conclude that “the issue of histogenesis [of MFH] is largely unresolvable”; it is “now regarded as synonymous with [high grade] undifferentiated pleomorphic sarcoma [HGUPS] and essentially represents a diagnosis of exclusion”. Yet despite this apparent lack of progress, the first decade of the 21st century has seen some significant progress in terms of defining the origins of MFH. Perhaps more importantly these origins might also pave the way for novel therapies. This manuscript will highlight MFH’s troubled history, discuss recent advances, comment as to what the coming years may promise, and what further needs to be done to make sure that progress continues.
Malignant fibrous histiocytoma (MFH); undifferentiated pleomorphic sarcomas; mesenchymal stem cells; differentiation therapy; classification
Bevacizumab is a humanized monoclonal antibody to VEGF, and the incorporation of bevacizumab to chemotherapy is one of the rapidly evolving areas in the treatment of breast cancer. Bevacizumab in combination with chemotherapy versus chemotherapy alone improves progression-free survival and increases the response rate in first-line therapy for locally recurrent or metastatic breast cancer. This approach has been and is still being evaluated for early breast cancer in neoadjuvant and adjuvant settings. Bevacizumab is well tolerated and has an established tolerability profile. Both tumor- and host-related biomarkers of bevacizumab activity, response and benefit are emerging from Phase I, II and III clinical trials. The biomarkers of benefit will ultimately help identify the subgroups of patients who specifically benefit from anti-VEGF therapy with bevacizumab.
bevacizumab; breast cancer; chemotherapy; clinical trials; first-line therapy; VEGF