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Nature Genetics Feb 2019Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types...
Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.
Topics: Antineoplastic Agents; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Mutation; Neoplasms; Tumor Burden
PubMed: 30643254
DOI: 10.1038/s41588-018-0312-8 -
Cancer Discovery Dec 2020Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, varies across malignancies. Panel...
Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, varies across malignancies. Panel sequencing-based estimates of TMB have largely replaced whole-exome sequencing-derived TMB in the clinic. Retrospective evidence suggests that TMB can predict the efficacy of immune checkpoint inhibitors, and data from KEYNOTE-158 led to the recent FDA approval of pembrolizumab for the TMB-high tumor subgroup. Unmet needs include prospective validation of TMB cutoffs in relationship to tumor type and patient outcomes. Furthermore, standardization and harmonization of TMB measurement across test platforms are important to the successful implementation of TMB in clinical practice. SIGNIFICANCE: Evaluation of TMB as a predictive biomarker creates the need to harmonize panel-based TMB estimation and standardize its reporting. TMB can improve the predictive accuracy for immunotherapy outcomes, and has the potential to expand the candidate pool of patients for treatment with immune checkpoint inhibitors.
Topics: Biomarkers, Tumor; Humans; Neoplasms; Tumor Burden
PubMed: 33139244
DOI: 10.1158/2159-8290.CD-20-0522 -
Cancer Cell Nov 2019Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader...
Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Lymphoma, Large-Cell, Anaplastic; Mice; Proteolysis; STAT3 Transcription Factor; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 31715132
DOI: 10.1016/j.ccell.2019.10.002 -
Blood Advances Oct 2020ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR)...
ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.
Topics: Antigens, CD19; Biological Products; Humans; Immunotherapy, Adoptive; Inflammation; Tumor Burden
PubMed: 33035333
DOI: 10.1182/bloodadvances.2020002394 -
Science (New York, N.Y.) May 2015How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer...
How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer genes in small (0.8 to 4.7 square millimeters) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultraviolet light. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected mutations were found in 18 to 32% of normal skin cells at a density of ~140 driver mutations per square centimeter. We observed variability in the driver landscape among individuals and variability in the sizes of clonal expansions across genes. Thus, aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis.
Topics: Carcinoma, Squamous Cell; Clonal Evolution; Epidermis; Eyelids; Genes, Neoplasm; Humans; Mutation; Neoplasms, Radiation-Induced; Selection, Genetic; Skin Neoplasms; Tumor Burden; Ultraviolet Rays
PubMed: 25999502
DOI: 10.1126/science.aaa6806 -
Seminars in Cancer Biology Apr 2015Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing... (Review)
Review
Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms.
Topics: Biomarkers, Tumor; Cell Differentiation; Cell Survival; Clonal Evolution; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplastic Stem Cells; Radiotherapy; Tumor Burden
PubMed: 25025713
DOI: 10.1016/j.semcancer.2014.07.001 -
Cancer Cytopathology Dec 2019
Review
Topics: Biomarkers, Tumor; DNA Mutational Analysis; Female; Humans; Male; Mutation; Neoplasms; Sensitivity and Specificity; Tumor Burden
PubMed: 31433548
DOI: 10.1002/cncy.22174 -
Frontiers in Immunology 2020Cancer immunotherapy has revolutionized the treatment landscape in medical oncology, but its efficacy has been variable across patients. Biomarkers to predict such... (Review)
Review
Cancer immunotherapy has revolutionized the treatment landscape in medical oncology, but its efficacy has been variable across patients. Biomarkers to predict such differential response to immunotherapy include cytotoxic T lymphocyte infiltration, tumor mutational burden, and microsatellite instability. A growing number of studies also suggest that baseline tumor burden, or tumor size, predicts response to immunotherapy. In this review, we discuss the changes in immune profile and therapeutic responses that occur with increasing tumor size. We also overview therapeutic approaches to reduce tumor burden and favorably modulate the immune microenvironment of larger tumors.
Topics: Humans; Immunotherapy; Neoplasms; Tumor Burden
PubMed: 33597954
DOI: 10.3389/fimmu.2020.629722 -
Cell Jun 2020Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for...
Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-β3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-β3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell β3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by β3-integrin, providing a previously unrecognized mechanism of cancer growth control.
Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Humans; Integrin beta3; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasms; Signal Transduction; Tumor Burden
PubMed: 32473126
DOI: 10.1016/j.cell.2020.02.003 -
American Society of Clinical Oncology... 2014At the root of science lie basic rules, if we can discover or deduce them. This is not an abstract project but practical; if we can understand the why then perhaps we... (Review)
Review
At the root of science lie basic rules, if we can discover or deduce them. This is not an abstract project but practical; if we can understand the why then perhaps we can rationally intervene. One of the unifying unsolved problems in physics is the hypothetical "Theory of Everything." In a similar vein, we can ask whether our own field contains such hidden fundamental truths and, if so, how we can use them to develop better therapies and outcomes for our patients. Modern oncology has developed as drugs and translational science have matured over the 50 years since ASCO's founding, but almost from that beginning tumor modeling has been a key tool. Through this general approach Norton and Simon changed our understanding of cancer biology and response to therapy when they described the fit of Gompertzian curves to both clinical and animal observations of tumor growth. The practical relevance of these insights has only grown with the development of DNA sequencing promising a raft of new targets (and drugs). In that regard, Larry Norton's contribution to this year's Educational Book reminds us to always think creatively about the fundamental problems of tumor growth and metastases as well as therapeutic response. Demonstrating the creativity and thoughtfulness that have marked his remarkable career, he now incorporates a newer concept of self-seeding to further explain why Gompertzian growth occurs and, in the process, provides a novel potential therapeutic target. As you read his elegantly presented discussion, consider how this understanding, wisely applied to the modern era of targeted therapies, might speed the availability of better treatments. But even more instructive is his personal model-not only the Norton-Simon Hypothesis-of how to live and approach science, biology, patients and their families, as well as the broader community. He shows that with energy, enthusiasm, optimism, intellect, and hard work we can make the world better. Clifford A. Hudis, MD, FACP, 2013-2014 ASCO President.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Drug Design; Humans; Models, Biological; Molecular Targeted Therapy; Neoplasms; Signal Transduction; Treatment Outcome; Tumor Burden
PubMed: 24857052
DOI: 10.14694/EdBook_AM.2014.34.3