78 research outputs found
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A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas
Background
Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy.
Methods
Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m2 weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m2 monthly).
Results
Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27–799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response.
Conclusions
Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted.
Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.asp
Emerging mechanisms of immunotherapy resistance in sarcomas
Sarcomas are a heterogeneous group of over 150 mesenchymal neoplasms of bone and soft tissue. Clinical prognosis remains poor in the metastatic and refractory setting, despite treatment with traditional chemotherapies. A subset of sarcoma patients can exhibit remarkable responses to novel immune therapies; however, most patients will not respond. Emerging data from genetic and transcriptomic datasets suggests that patients who are resistant to checkpoint inhibitor monotherapy may have low expression of immune-related genes, suggesting that the sarcoma was not sufficiently immunogenic to trigger or maintain an immune response to generate tumor-specific immune effector cells. In this review, we discuss the emerging data surrounding potential mechanisms of resistance, including various biomarkers explored in clinical trials of immune therapy for sarcomas. We also review future directions in clinical trials that are focused on boosting tumor immunogenicity to improve the activity of checkpoint inhibitors, as well as adoptive cellular therapy approaches to bypass deficiencies in neoantigens or antigen presentation
Value added: functional MR imaging in management of bone and soft tissue sarcomas
MRI plays a crucial role in the initial diagnosis, treatment planning, and long-term management of bone and soft tissue sarcomas. Technological advances have enabled improvements in both delineation of anatomic detail, and in functional imaging techniques that interrogate tissues at the cellular level. This bears particular relevance in sarcomas as morphological parameters alone do not necessarily correlate with treatment response and prognosis. Here, we describe recent developments in advanced MRI techniques, including chemical-shift MRI, diffusion-weighted imaging (DWI), MR spectroscopy (MRS), and dynamic contrast enhanced (DCE) MRI.
Chemical-shift MRI allows robust discrimination of marrow infiltrating neoplasms from benign red marrow. DWI reveals tumor cellularity, and aids in distinguishing benign and malignant tumors along with the assessment of treatment response. MRS is technically challenging in the musculoskeletal system, but shows promise as a means to noninvasively assess metabolic aberrations in a variety of sarcomas. DCE is particularly suited to treatment response evaluation, in which traditional size-based assessment criteria may underestimate efficacy in clinical trials.
Functional MRI techniques offer novel imaging biomarkers that effectively complement conventional MRI in the assessment of bone and soft tissue sarcomas at all stages of patient care
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Future directions in soft tissue sarcoma treatment
Sarcoma is a broad term for mesenchymal malignancies that arise from soft tissue or bone. Despite classification by histologic subtype, clinical behavior and response to therapy have great variability. Modern genetic sequencing techniques have been able to identify additional genetic variability and subsequently new targeted therapies. In this review, we discuss the current state of STS diagnostics and treatment and explore some of the more promising areas in which progress is being made. We discuss therapies targeting PDGFRα/KIT, β-Catenin/APC/NOTCH, IDH-1/2 mutations, MDM2 amplifications, EZH2/INI1 expression loss, ALK fusion, and ASPSCR1-TFE3 fusion. We also discuss the progress that has been made within immunotherapies. While soft tissue sarcomas still portend a poor prognosis, these targeted therapies and immunotherapies provide treatment with less toxic side effects
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Emerging Role for Precision Therapy Through Next-Generation Sequencing for Sarcomas
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Precision medicine in gastrointestinal stromal tumors
Gastrointestinal stromal tumors (GISTs) are rare soft tissue sarcomas of the gastrointestinal tract, with most carrying conserved driver mutations in the tyrosine kinase receptors KIT or PDGFRα. The use of targeted therapy against these mutations in GISTs is one of the most successful examples of precision medicine in solid tumors, beginning in 2002 with the development of imatinib, a small molecule tyrosine kinase inhibitor (TKI) of KIT. In recent years, much progress has been made in understanding the molecular mechanisms of GISTs while unveiling their genetic heterogeneity. Since development of secondary mutations leads to imatinib resistance, the majority of research efforts have focused on identification of novel inhibitors to improve outcomes in imatinib-resistant GISTs. Sunitinib and regorafenib are two TKIs with demonstrated activity after failure of imatinib, which led to the U.S. FDA approval. Pivotal phase 3 clinical trials are ongoing with two novel agents, avapritinib and ripretinib, based on their remarkable activities in the 4th or greater line settings in phase 1/2 studies of these drugs. In this review, we will outline the remarkable diversity of genetic mutations in GISTs, and review the evidence for treatment options of genomic medicine in locally advanced or metastatic gastrointestinal stromal tumors
Latest advances in adult gastrointestinal stromal tumors
Gastrointestinal stromal tumors (GISTs) are the most common GI tract mesenchymal tumors. GIST patients are optimally managed by a precision medicine approach. Herein, we discuss the latest advances in precision medicine and ongoing clinical trials relevant to GIST. Circulating tumor DNA for detection of mutational changes could replace tissue biopsies and radiographic imaging once validated. Most GISTs are KIT/PDGFRα mutated, and despite the good clinical response to imatinib, treatment is generally not curative, more often due to secondary mutations. New mechanisms to bypass this resistance by inhibiting KIT downstream pathways and by targeting multiple KIT or PDGFRα mutations are being investigated. Immunotherapy for GIST patients is in its infancy. These approaches may lead to more effective, less toxic therapies
Growing Pains: a Simulation-Based Curriculum for Improving the Transition to Hematology/Oncology Fellowship
Trainee exposure to clinical oncology during residency training is heterogeneous and often modest. The steep learning curve upon entry into fellowship can result in undue stress for fellows and their patients. Simulation-based training has been shown to be superior to classical didactic approaches. We have introduced several innovative simulation-based workshops into the curriculum for the Johns Hopkins Hematology/Oncology Fellowship Training Program in order to address this unmet need. During the first months of training, fellows were engaged in activities emphasizing essential clinical and procedural skills. Specific workshops included the following: (1) chemotherapy writing, (2) cadaveric and simulation-based bone marrow biopsy and intrathecal chemotherapy administration, and (3) simulation-based communication skills training. All first-year fellows in our program participated in these exercises. Pre- and post-workshop surveys were administered to assess knowledge, attitudes, and behaviors; additional distant post-workshop evaluations were disseminated to assess the durability/impact of the curricula and for program evaluation. Overall, participating fellows indicated that the workshops improved patient care and comfort with procedures and patient-centered communication. Continued implementation of these workshops was recommended for program improvement. To the best of our knowledge, ours is amongst the first oncology fellowship training programs to systematically implement simulation-based curricula into our schema for fellowship training. We hypothesize that proactively introducing fellows to these high-yield activities will translate into improved patient care and reduced stress for trainees. Additional investigation into the long-term impact of such curricula remains an area of ongoing need
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Abstract A77: RNA helicase DDX3 – A novel therapeutic target in sarcoma
Abstract
High grade sarcomas are among the most common solid tumors in childhood. Although intensive chemotherapy has dramatically improved the outcome of children with localized osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma, the prognosis for children with metastatic or recurrent disease remains dismal, with no substantial improvement since the introduction of multi-agent chemotherapy regimens 30 years ago. The identification of novel therapeutic targets, and the development of drugs to exploit these targets, is therefore an urgent need. RNA helicases are ubiquitous enzymes, aberrantly expressed in a variety of solid and hematologic malignancies, that are involved in all aspects of RNA metabolism, including transcription, translation, mRNA splicing, and regulation of other protein-RNA interactions. The RNA helicase DDX3 is essential for translation of key cell cycle regulatory mRNA transcripts including cyclin A, cyclin E1, TGFB1, STAT1 and others. Expression of DDX3 is dramatically upregulated in mammary epithelial cells exposed to BPDE, a toxin found in cigarette smoke, and overexpression of DDX3 in breast cancer cell lines correlates with invasiveness and aggressive activity. MCF10a mammary epithelial cells induced to overexpress DDX3 undergo epithelial-mesenchymal transition (EMT) with increased invasive behavior, motility, and colony-forming activity, consistent with neoplastic transformation. Novel DDX3 mutations have recently been identified in medulloblastoma. These data suggest DDX3 may play a key role in the development and progression of a wide variety of solid tumors. We therefore investigated DDX3 expression in sarcomas. We found that sarcomas, both cell lines and primary samples, commonly express high levels of DDX3. Knock down of DDX3 expression in cell lines impaired proliferation, clonogenic activity in soft agar, sphere formation when grown under nonadherent conditions, and tumorigenicity in immune deficient mice. We have developed a novel DDX3 inhibitor, known as RK-33, that binds to the ATP binding domain and impairs helicase activity in a DNA unwinding assay. We found that RK-33 is selectively cytotoxic to sarcoma cell lines, compared with normal mesenchymal cells, and that sensitivity correlates with DDX3 expression. Importantly, Ewing sarcoma cells with a stem-like phenotype, characterized by high expression of aldehyde dehydrogenase, are as sensitive to RK-33 as the bulk population, despite being resistant to standard cytotoxic agents. Finally, we found that RK-33 suppresses the growth of human sarcomas in a murine xenograft model, and that sensitivity correlates with DDX3 expression. Thus, we have evidence that the RNA helicase DDX3 is an important mediator of sarcoma proliferation and tumorigenesis, and that inhibition of DDX3 with the small molecule RK-33 is a novel way to target chemotherapy-resistant sarcomas.
Citation Format: David M. Loeb, Breelyn A. Wilky, Catherine Kim, Elizabeth Montgomery, Venu Raman. RNA helicase DDX3 – A novel therapeutic target in sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A77
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