Claudia Valverde

Molecular basis for the treatment of renal cell carcinoma

Renal cell carcinoma (RCC) is a heterogeneous malignancy whose incidence rate has notably increased in recent years without any evident reason. Traditionally, RCC has been resistant to classic treatments (chemotherapy, radiotherapy and hormonal therapy), with only a small percentage of patients benefiting from cytokine therapy. Different hereditary syndromes have been associated with RCC, Von Hippel Lindau (VHL) being the most important syndrome. Understanding key molecular pathways implicated in the tumorigenesis of RCC has crystallised in the development of more effective therapies. Specifically, drugs targeting VEGF (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib) and PI3K-mTOR (temsirolimus and everolimus) have become the cornerstone of renal cancer treatment.

RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas.

Undifferentiated pleomorphic sarcoma (UPS) constitutes the most common subtype of soft tissue sarcoma. However, UPS is clinically and molecularly poorly understood, in great extent due to its intrinsic phenotypic and cytogenetic complexity, which in turn results in the absence of specific prognostic or predictive biomarkers. The RAS/mitogen‐activated protein kinases (MAPK) and phosphoinositide 3‐kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are considered to be 2 major mechanisms for sarcoma proliferation and survival and to the authors knowledge their role in UPS remains unclear. The objective of the current study was to investigate whether the RAS/MAPK and PI3K/mTOR pathways are activated in UPS, and whether pathway activation is associated with outcome.

Management and interpretation of novel toxicities of molecular targeted therapies: Renal toxicities

Over the past years the benefits and risks associated with pharmaceutical agents have received increasing attention from the medical community. Some doubts have arisen concerning the current approach of drug approval based on clinical trials. In most cases these studies include relatively small numbers of patients, which can lead to an incomplete safety profile assessment of these drugs at the time of approval. In addition, safety profile and effectiveness may change when these drugs are used in a wider, less carefully selected population than patients included in clinical trials. This phenomenon has been discussed in detail by Giezen and colleagues [1] in a recent publication. In this study of 174 biological products (antibodies, hormones, enzymes) approved from January 1995 through June 2007, including 136 agents approved in the US, 105 approved in the European Union, and 67 approved in both regions, the authors found 82 safety-related regulatory actions. The probability of a biological agent having a first safety-related regulatory action was 14% at 3 years and 29% at 10 years after approval. This is very important in cancer treatment in which major advances have been made in recent years with new targeted molecules such as antibodies (ABs) and tyrosine kinase inhibitors (TKIs). Most patients will be treated with these compounds for a long period of time and in such circumstances cumulative toxicities will appear. In our opinion, one has to be alert for new signs and symptoms reported by patients who are treated with these drugs. As an example, kidney cancer treatment has evolved in the last 3 years, and this change has been made thanks to the development of new drugs. During 2006 and 2007, four drugs were approved to treat kidney cancer: bevacizumab, sorafenib, sunitinib and temsirolimus. Bevacizumab toxicity is better known because many patients have been treated with it for other indications like colon, breast and lung cancer before its approval in renal cell cancer. However, the approval by the US Food and Drugs Administration (FDA) and the European Medicines Agency (EMEA) of sorafenib, sunitinib and temsirolimus was based on less than 3000 patients. Surprisingly, only 1242 patients have been treated with sorafenib (137 patients in phase I; 202 patients in phase II and 903 patients in one phase III study); 884 patients with sunitinib (28 patients in phase I, 106 in phase II and 750 in phase III studies) and 761 patients with temsirolimus (24 in a phase I study, 111 in phase II and 626 patients in the phase III study). Under such circumstances, little is known about the chronic toxicities of these drugs. In a recent study, Bhojani and colleagues [2] reviewed the main toxicities reported in phase I, II and III studies of three drugs approved, in different settings, for kidney cancer. The authors found that renal toxicities were rare and included proteinuria and oedema. However, proteinuria may occur after prolonged exposure. Other molecules included were bortezomib, erlotinib and lapatinib. As previously mentioned, the approval of different inhibitors that target the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) has changed the treatment of cancer patients. However, because the same growth factors are expressed in the kidney, these therapeutic agents have renal side effects. In this paper, we will review renal toxicities related to molecular targeted therapies according to their different nephron structural damage. We will also point out the probable pathogenesis, early diagnosis and treatment.

Do patients with metastatic urothelial carcinoma benefit from docetaxel as second-line chemotherapy?

PurposeTo evaluate the efficacy and toxicity of docetaxel regimen as second-line after failure of a platinum-based chemotherapy.MethodsBetween May 2005 and June 2008, we retrospectively analyzed the data of 22 patients who had evidence of disease progression after one prior platinum-based regimen for metastatic urothelial carcinoma. Patients were treated with two different docetaxel dose schedules: (1) docetaxel 60xa0mg/m2 every 21xa0days for unfit patients or (2) docetaxel 75xa0mg/m2 every 21xa0days for fit patients.ResultsMedian number of docetaxel cycles was three. Overall disease control rate was 18xa0%. Of the 22 patients, no patient achieved complete or partial response and four patients had stable disease. Median progression-free survival was 1.67xa0months and median overall survival was 3.12xa0months. Neutropenia was the most common adverse event.ConclusionsThis study identifies that docetaxel as second-line chemotherapy has low activity and was associated with significant toxicity.

Emerging therapies for urothelial cancer.

Urothelial carcinoma is one of the leading causes of death in Europe and the United States. Despite its chemosensitivity, median overall survival for advanced disease is still nearly 1 year. Most second-line chemotherapeutic agents tested have been disappointing. Thus, new treatment strategies are clearly needed. This review focuses on emerging therapies in urothelial carcinoma. Results from recent clinical trials, investigating the activity of new generation cytostatic agents, as well as results from studies assessing the toxicity and efficacy of novel targeted therapies, are discussed. In this setting, anti-epidermal growth factor receptor, angiogenesis, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors account for the majority of phase I and II trials.

Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS).

BackgroundnPatients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients.nnnPatients and methodsnA multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5u2009mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome.nnnResultsnThirty-five patients were enrolled and received at least one cycle. PFSR at 4u2009months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival.nnnConclusionnGemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.

Epidermal growth factor receptor (EGFR) inhibitors in gastrointestinal cancer.

Gastrointestinal (GI) cancer continues to be a leading cause of cancer morbidity and mortality worldwide. Over the past decade the treatment options for patients with GI cancers have increased with the advent of newer combination chemotherapy regimes. Despite these clinical advances, new strategies are warranted in order to improve the efficacy as well as the safety. New molecular targets have provided novel opportunities in the treatment of GI cancer. One of the most advanced new approaches to date is the use of targeted inhibitors of the epidermal growth factor receptor (EGFR). In this review we describe the current status of therapeutic strategies based on EGFR inhibitors in the treatment of GI cancer.

Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial driver for GIST tumor initiation, transformation, and cancer cell proliferation. Three tyrosine kinase inhibitors (TKIs) with KIT inhibitory activity – imatinib, sunitinib, and regorafenib – are approved to treat advanced GIST and have successfully exploited this addiction to KIT oncogenic signaling, demonstrating remarkable activity in a disease that historically had no successful systemic therapy options. However, GIST refractory to approved TKIs remain an unmet clinical need, as virtually all patients with metastatic GIST eventually progress on any given therapy. The main and best-established mechanism of resistance is the polyclonal expansion of multiple subpopulations harboring different secondary KIT mutations. The present review aims at summarizing current and forthcoming treatment directions in advanced imatinib-resistant GIST supported by a strong biological rationale.

SEOM Clinical Guideline of management of soft-tissue sarcoma (2016)

Soft-tissue sarcomas are uncommon and heterogeneous tumors of mesenchymal origin. A soft-tissue mass that is increasing in size, greater than 5xa0cm, or located under deep fascia are criteria for suspicion of sarcoma. Diagnosis, treatment, and management should preferably be performed by a multidisciplinary team in reference centers. MRI and lung CT scan are mandatory for local and distant assessment. A biopsy indicating histological type and grade is needed previous to the treatment. Wide surgical resection with tumor-free tissue margin is the primary treatment for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not likely of being improved with reexcision. Neoadjuvant and adjuvant chemotherapy improve survival in selected cases, usually in high-grade sarcomas of the extremities. In the case of metastatic disease, patients with exclusive lung metastasis could be considered for surgery. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. New drugs have shown activity in second-line therapy and in specific histological subtypes.

Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer: Genetic basis of TGCT

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case–control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann–Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (ORu2009=u20096.28, pu2009=u20096.42 × 10−23) (p.Arg2016Trp), EXO5 (ORu2009=u20093.37, pu2009=u20094.82 × 10−09) (p.Arg344AlafsTer10) and DNAH7 (ORu2009=u20091.64, pu2009=u20090.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.