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Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients."
http://www.sciencedirect.com/science/ar ... 7415003177
Review Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential
Re: Review Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential
“Main Text
Introduction
The scientific community united against a common enemy in 1971 when President Nixon signed a bill initiating the “War on Cancer,” which provided funding for scientific research focused on improving our understanding and treatment of cancer. Without doubt, the intervening years were followed by great advances in the elucidation of the molecular mechanisms that regulate growth and death of normal cells, including a deep understanding of how these pathways progressively go awry during the development of cancer. This understanding led to the era of genomically targeted therapies and “precision medicine” in the treatment of cancer. Genomically targeted therapies can result in remarkable clinical responses. The ability of cancer cells to adapt to these agents by virtue of their genomic instability and other resistance mechanisms eventually leads to disease progression in the majority of patients nonetheless. Unraveling the mechanisms by which cancer cells become resistant to drugs and developing new agents to target the relevant pathways have become logical next steps in this approach for cancer treatment. However, given the genetic and epigenetic instability of cancer cells, it is likely that each new drug or combination of drugs targeting the tumor cells will meet with more complex mechanisms of acquired resistance. Recent findings suggest that T cells, bearing antigen receptors that are generated by random rearrangement of gene segments, followed by selective processes that result in a vast repertoire of T cell clones, provide sufficient diversity and adaptability to match the complexity of tumors. Discoveries regarding regulation of T cell responses have provided key principles regarding immune checkpoints that are being translated into clinical success, with durable responses and long-term survival greater than 10 years in a subset of patients with metastatic melanoma, as well as yielding promising results in several other tumor types. Now, with the perspective of combining genomically targeted agents and immune checkpoint therapies, we are finally poised to deliver curative therapies to cancer patients. To support this goal and accelerate these efforts, changes in directions of research support and funding may be required.”
Introduction
The scientific community united against a common enemy in 1971 when President Nixon signed a bill initiating the “War on Cancer,” which provided funding for scientific research focused on improving our understanding and treatment of cancer. Without doubt, the intervening years were followed by great advances in the elucidation of the molecular mechanisms that regulate growth and death of normal cells, including a deep understanding of how these pathways progressively go awry during the development of cancer. This understanding led to the era of genomically targeted therapies and “precision medicine” in the treatment of cancer. Genomically targeted therapies can result in remarkable clinical responses. The ability of cancer cells to adapt to these agents by virtue of their genomic instability and other resistance mechanisms eventually leads to disease progression in the majority of patients nonetheless. Unraveling the mechanisms by which cancer cells become resistant to drugs and developing new agents to target the relevant pathways have become logical next steps in this approach for cancer treatment. However, given the genetic and epigenetic instability of cancer cells, it is likely that each new drug or combination of drugs targeting the tumor cells will meet with more complex mechanisms of acquired resistance. Recent findings suggest that T cells, bearing antigen receptors that are generated by random rearrangement of gene segments, followed by selective processes that result in a vast repertoire of T cell clones, provide sufficient diversity and adaptability to match the complexity of tumors. Discoveries regarding regulation of T cell responses have provided key principles regarding immune checkpoints that are being translated into clinical success, with durable responses and long-term survival greater than 10 years in a subset of patients with metastatic melanoma, as well as yielding promising results in several other tumor types. Now, with the perspective of combining genomically targeted agents and immune checkpoint therapies, we are finally poised to deliver curative therapies to cancer patients. To support this goal and accelerate these efforts, changes in directions of research support and funding may be required.”
Last edited by D.ap on Sun Nov 19, 2017 11:33 am, edited 1 time in total.
Debbie
Re: Review Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential
“Precision Medicine: Targeting the Drivers
In the past three decades, enormous strides have been made in elucidating the molecular mechanisms involved in the development of cancer (Hanahan and Weinberg, 2011). It is now clear that the oncogenic process involves somatic mutations that result in activation of genes that are normally involved in regulation of cell division and programmed cell death, as well as inactivation of genes involved in protection against DNA damage or driving apoptosis (Bishop, 1991; Solomon et al., 1991; Weinberg, 1991; Knudson, 2001). These genetic links led to the decision early in the war on cancer to undertake sequencing of cancer genomes to provide a comprehensive view of somatic mutational landscapes in cancer and identify possible therapeutic targets. Infrastructure and funding were provided to coordinate the sequencing efforts. It has become apparent that the level of somatic mutations differs widely between and within different tumor types ranging from very low rates in childhood leukemias to very high rates in tumors associated with carcinogens (Alexandrov et al., 2013).”
In the past three decades, enormous strides have been made in elucidating the molecular mechanisms involved in the development of cancer (Hanahan and Weinberg, 2011). It is now clear that the oncogenic process involves somatic mutations that result in activation of genes that are normally involved in regulation of cell division and programmed cell death, as well as inactivation of genes involved in protection against DNA damage or driving apoptosis (Bishop, 1991; Solomon et al., 1991; Weinberg, 1991; Knudson, 2001). These genetic links led to the decision early in the war on cancer to undertake sequencing of cancer genomes to provide a comprehensive view of somatic mutational landscapes in cancer and identify possible therapeutic targets. Infrastructure and funding were provided to coordinate the sequencing efforts. It has become apparent that the level of somatic mutations differs widely between and within different tumor types ranging from very low rates in childhood leukemias to very high rates in tumors associated with carcinogens (Alexandrov et al., 2013).”
Debbie
Re: Review Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential
Genetic Diversity in Alveolar Soft Part Sarcoma: A Subset Contain Variant Fusion Genes, Highlighting Broader Molecular Kinship with Other MiT Family Tumors
Abstract
Alveolar soft part sarcoma (ASPS) is a rare malignancy that, since its initial description, remains a neoplasm of uncertain histogenesis. The disease-defining molecular event characterizing the diagnosis of ASPS is the ASPSCR1-TFE3 fusion gene. Following identification of an index case of ASPS with a novel TFE3 fusion partner, we performed a retrospective review to determine whether this represents an isolated event. We identified two additional cases, for a total of three cases lacking ASPSCR1 partners. The average patient age was 46 years (range, 17–65); two patients were female. The sites of origin included the transverse colon, foot, and dura. Each case exhibited a histomorphology typical of ASPS, and immunohistochemistry was positive for TFE3 in all cases. Routine molecular testing of the index patient demonstrated a HNRNPH3-TFE3 gene fusion; the remaining cases were found to have DVL2-TFE3 or PRCC-TFE3 fusion products. The latter two fusions have previously been identified in renal cell carcinoma; to our knowledge this is the first report of a HNRNPH3-TFE3 gene fusion. These findings highlight a heretofore underrecognized genetic diversity in ASPS, which appears to more broadly molecularly overlap with that of translocation-associated renal cell carcinoma and PEComa. These results have immediate implications in the diagnosis of ASPS since assays reliant upon ASPSCR1 may yield a false negative result. While these findings further understanding of the molecular pathogenesis of ASPS, issues related to the histogenesis of this unusual neoplasm remain unresolved.
Keywords: Alveolar soft part sarcoma, ASPSCR1, TFE3, HNRNPH3, DVL2, PRCC, fusion
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057290/
Abstract
Alveolar soft part sarcoma (ASPS) is a rare malignancy that, since its initial description, remains a neoplasm of uncertain histogenesis. The disease-defining molecular event characterizing the diagnosis of ASPS is the ASPSCR1-TFE3 fusion gene. Following identification of an index case of ASPS with a novel TFE3 fusion partner, we performed a retrospective review to determine whether this represents an isolated event. We identified two additional cases, for a total of three cases lacking ASPSCR1 partners. The average patient age was 46 years (range, 17–65); two patients were female. The sites of origin included the transverse colon, foot, and dura. Each case exhibited a histomorphology typical of ASPS, and immunohistochemistry was positive for TFE3 in all cases. Routine molecular testing of the index patient demonstrated a HNRNPH3-TFE3 gene fusion; the remaining cases were found to have DVL2-TFE3 or PRCC-TFE3 fusion products. The latter two fusions have previously been identified in renal cell carcinoma; to our knowledge this is the first report of a HNRNPH3-TFE3 gene fusion. These findings highlight a heretofore underrecognized genetic diversity in ASPS, which appears to more broadly molecularly overlap with that of translocation-associated renal cell carcinoma and PEComa. These results have immediate implications in the diagnosis of ASPS since assays reliant upon ASPSCR1 may yield a false negative result. While these findings further understanding of the molecular pathogenesis of ASPS, issues related to the histogenesis of this unusual neoplasm remain unresolved.
Keywords: Alveolar soft part sarcoma, ASPSCR1, TFE3, HNRNPH3, DVL2, PRCC, fusion
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057290/
Debbie
Re: Review Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential
INTRODUCTION
Alveolar soft part sarcoma (ASPS) is a rare neoplasm that can occur at virtually any age but tends to predominate among young adults.1–5 It most often arises in the deep soft tissues of the extremities and trunk – particularly the thigh – although other locations such as the head and neck, and viscera are occasional sites of origin.1–5 Tumors are associated with a risk of local recurrence; however, they are notorious for both early and late metastases, particularly involving the lung, bone, and brain.1,2,4,5
Morphologically tumors are characteristically composed of polygonal cells with a nested to organoid pattern, which is separated by delicate fibrovascular septa.6 Centrally there is often necrosis and concomitant loss of cell cohesion resulting in the pseudoalveolar pattern from which its name is derived.7 The cells have abundant granular eosinophilic to clear cytoplasm. The nuclei are generally round and monomorphic with a prominent nucleolus; mitotic activity is typically inconspicuous. ASPS has heretofore been reported to be genetically defined by der(17)t(X;17)(p11;q25), resulting in an ASPSCR1-TFE3 fusion gene.6 Herein we report three cases of alveolar soft part sarcoma containing TFE3 gene fusion partners other than ASPSCR1.
Alveolar soft part sarcoma (ASPS) is a rare neoplasm that can occur at virtually any age but tends to predominate among young adults.1–5 It most often arises in the deep soft tissues of the extremities and trunk – particularly the thigh – although other locations such as the head and neck, and viscera are occasional sites of origin.1–5 Tumors are associated with a risk of local recurrence; however, they are notorious for both early and late metastases, particularly involving the lung, bone, and brain.1,2,4,5
Morphologically tumors are characteristically composed of polygonal cells with a nested to organoid pattern, which is separated by delicate fibrovascular septa.6 Centrally there is often necrosis and concomitant loss of cell cohesion resulting in the pseudoalveolar pattern from which its name is derived.7 The cells have abundant granular eosinophilic to clear cytoplasm. The nuclei are generally round and monomorphic with a prominent nucleolus; mitotic activity is typically inconspicuous. ASPS has heretofore been reported to be genetically defined by der(17)t(X;17)(p11;q25), resulting in an ASPSCR1-TFE3 fusion gene.6 Herein we report three cases of alveolar soft part sarcoma containing TFE3 gene fusion partners other than ASPSCR1.
Debbie