Special Conference on Tumor Immunology and Immunotherapy: A New Chapter.
Byrne Katelyn T,Vonderheide Robert H,Jaffee Elizabeth M,Armstrong Todd D
Cancer immunology research
The overall objective of the fifth American Association for Cancer Research Special Conference, "Tumor Immunology and Immunotherapy: A New Chapter," organized by the Cancer Immunology Working Group, was to highlight multidisciplinary approaches of immunotherapy and mechanisms related to the ability of immunotherapy to fight established tumors. With the FDA approval of sipuleucel-T, ipilimumab (anti-CTLA-4; Bristol-Myers Squibb), and the two anti-PD-1 antibodies, pembrolizumab (formerly MK-3475 or lambrolizumab; Merck) and nivolumab (Bristol-Myers Squibb), immunotherapy has become a mainstream treatment option for some cancers. Many of the data presented at the conference and reviewed in this article showcase the progress made in determining the mechanistic reasons for the success of some treatments and the mechanisms associated with tolerance within the tumor microenvironment, both of which are potential targets for immunotherapy. In addition to combination and multimodal therapies, improvements in existing therapies will be needed to overcome the numerous ways that tumor-specific tolerance thwarts the immune system. This conference built upon the success of the 2012 conference and focused on seven progressing and/or emerging areas-new combination therapies, combination therapies and vaccine improvement, mechanisms of antibody therapy, factors in the tumor microenvironment affecting the immune response, the microbiomes effect on cancer and immunotherapy, metabolism in immunotherapy, and adoptive T-cell therapy. Cancer Immunol Res; 3(6); 1-8. ©2015 AACR.
10.1158/2326-6066.CIR-15-0106
Ultrasound in tumor immunotherapy: Current status and future developments.
Ho Yi-Ju,Li Ju-Pi,Fan Ching-Hsiang,Liu Hao-Li,Yeh Chih-Kuang
Journal of controlled release : official journal of the Controlled Release Society
Immunotherapy has considerable potential in eliminating cancers by activating the host's own immune system, while the thermal and mechanical effects of ultrasound have various applications in tumor therapy. Hyperthermia, ablation, histotripsy, and microbubble stable/inertial cavitation can alter the tumor microenvironment to enhance immunoactivation to inhibit tumor growth. Microbubble cavitation can increase vessel permeability and thereby improve the delivery of immune cells, cytokines, antigens, and antibodies to tumors. Violent microbubble cavitation can disrupt tumor cells and efficiently expose them to numerous antigens so as to promote the maturity of antigen-presenting cells and subsequent adaptive immune-cell activation. This review provides an overview and compares the mechanisms of ultrasound-induced immune modulation for peripheral and brain tumor therapy, even degenerative brain diseases therapy. The possibility of reversing tumors to an immunoactive microenvironment by utilizing the cavitation of microbubbles loaded with therapeutic gases is also proposed as another potential pathway for immunotherapy. Finally, we disuss the challenges and opportunities of ultrasound in immunotherapy for future development.
10.1016/j.jconrel.2020.04.023
Targeted therapies to improve tumor immunotherapy.
Begley Jonathan,Ribas Antoni
Clinical cancer research : an official journal of the American Association for Cancer Research
Durable tumor regression and potential cures of metastatic solid cancers can be achieved by a variety of cellular immunotherapy strategies, including cytokine therapy, dendritic cell-based vaccines, and immune-activating antibodies, when used in so-called immune-sensitive cancers such as melanoma and renal cell carcinoma. However, these immunotherapy strategies have very low tumor response rates, usually in the order of 5% to 10% of treated patients. We propose that the antitumor activity of adequately stimulated tumor antigen-specific T cells is limited by local factors within the tumor milieu and that pharmacologic modulation of this milieu may overcome tumor resistance to immunotherapy. By understanding the mechanisms of cancer cell immune escape, it may be possible to design rational combinatorial approaches of novel therapies able to target immunosuppressive or antiapoptotic molecules in an attempt to reverse resistance to immune system control. We term this mode of treatment "immunosensitization." Ideal candidates for immunosensitizing drugs would be targeted drugs that block key oncogenic mechanisms in cancer cells resulting in a proapoptotic cancer cell milieu and at the same time do not negatively interfere with critical lymphocyte functions.
10.1158/1078-0432.CCR-07-4804
Immunotherapy and tumor microenvironment.
Tang Haidong,Qiao Jian,Fu Yang-Xin
Cancer letters
Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases.
10.1016/j.canlet.2015.10.009
Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential?
Journal for immunotherapy of cancer
The immunologic landscape of the host and tumor play key roles in determining how patients will benefit from immunotherapy, and a better understanding of these factors could help inform how well a tumor responds to treatment. Recent advances in immunotherapy and in our understanding of the immune system have revolutionized the treatment landscape for many advanced cancers. Notably, the use of immune checkpoint inhibitors has demonstrated durable responses in various malignancies. However, the response to such treatments is variable and currently unpredictable, the availability of predictive biomarkers is limited, and a substantial proportion of patients do not respond to immune checkpoint therapy. Identification and investigation of potential biomarkers that may predict sensitivity to immunotherapy is an area of active research. It is envisaged that a deeper understanding of immunity will aid in harnessing the full potential of immunotherapy, and allow appropriate patients to receive the most appropriate treatments. In addition to the identification of new biomarkers, the platforms and assays required to accurately and reproducibly measure biomarkers play a key role in ensuring consistency of measurement both within and between patients. In this review we discuss the current knowledge in the area of peripheral immune-based biomarkers, drawing information from the results of recent clinical studies of a number of different immunotherapy modalities in the treatment of cancer, including checkpoint inhibitors, bispecific antibodies, chimeric antigen receptor T cells, and anti-cancer vaccines. We also discuss the various technologies and approaches used in detecting and measuring circulatory biomarkers and the ongoing need for harmonization.
10.1186/s40425-019-0799-2
Up-regulation of PCOLCE by TWIST1 promotes metastasis in Osteosarcoma.
Wang Shang,Zhong Li,Li Yin,Xiao Desheng,Zhang Ruhua,Liao Dan,Lv Dongming,Wang Xin,Wang Juanfei,Xie Xianbiao,Chen Jing,Wu Yuanzhong,Kang Tiebang
Theranostics
Procollagen C-proteinase enhancer protein (PCOLCE) was originally identified as an enhancer to facilitate the catalysis of procollagens by BMP1. PCOLCE participates in the reconstitution of extracellular and corneal repair. The elevation of PCOLCE in blood indicates that breast cancer has metastasized into the bones. However, direct research on PCOLCE has not been reported. : ECM candidates were identified by RNA-seq analysis from 4 normal and 16 osteosarcoma tissues. The migration and invasion abilities of osteosarcoma cells were determined by a Transwell assay. A spontaneous metastatic osteosarcoma model was established to assess osteosarcoma metastasis . The N-linked glycosylated amino acids were identified by PNGase F treatment combined with Western blotting. The mechanism of TWIST1 regulating PCOLCE transcription was elucidated by luciferase, qPCR and ChIP assays. : PCOLCE was markedly up-regulated in human osteosarcoma tissues compared to its expression in noncancerous adjacent tissues; high expression in tissues correlated with a poor patient prognosis, and the knockdown of by shRNAs impaired the migration, invasion and lung metastasis of osteosarcoma cells. The overexpression of wild-type PCOLCE, but not its N29Q mutant, promoted migration, invasion and metastasis, indicating that the glycosylation of PCOLCE at Asn29 is necessary for its functions in osteosarcoma. TWIST1 a key transcription factor in metastasis, was also overexpressed in osteosarcoma tissues and positively correlated with either PCOLCE or its potential procollagen substrates, such as COL1A1, COL1A2, COL5A1, COL8A2 and COL10A1. : Our findings are the first to provide evidence that PCOLCE plays a critical role in promoting the lung metastasis of osteosarcoma, and this up-regulation of PCOLCE by TWIST1 may lead to a new therapeutic strategy to treat patients with metastatic osteosarcoma.
10.7150/thno.34090
Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma.
Wang Xin,Qin Ge,Liang Xiaoting,Wang Wen,Wang Zhuo,Liao Dan,Zhong Li,Zhang Ruhua,Zeng Yi-Xin,Wu Yuanzhong,Kang Tiebang
Nature communications
Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis.
10.1038/s41467-020-14870-4
Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma.
Scott Milcah C,Temiz Nuri A,Sarver Anne E,LaRue Rebecca S,Rathe Susan K,Varshney Jyotika,Wolf Natalie K,Moriarity Branden S,O'Brien Timothy D,Spector Logan G,Largaespada David A,Modiano Jaime F,Subramanian Subbaya,Sarver Aaron L
Cancer research
Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades, and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of intertumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and to improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans ( = 49), mice ( = 103), and dogs ( = 34) were generated using RNA sequencing. Conserved intertumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel gene cluster expression summary score (GCESS) to quantify intertumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas. Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients. This study offers new tools to quantify tumor heterogeneity in osteosarcoma, identifying potentially useful prognostic biomarkers for metastatic progression and survival in patients. .
10.1158/0008-5472.CAN-17-0576
Trabectedin Overrides Osteosarcoma Differentiative Block and Reprograms the Tumor Immune Environment Enabling Effective Combination with Immune Checkpoint Inhibitors.
Ratti Chiara,Botti Laura,Cancila Valeria,Galvan Silvia,Torselli Ilaria,Garofalo Cecilia,Manara Maria Cristina,Bongiovanni Lucia,Valenti Cesare F,Burocchi Alessia,Parenza Mariella,Cappetti Barbara,Sangaletti Sabina,Tripodo Claudio,Scotlandi Katia,Colombo Mario P,Chiodoni Claudia
Clinical cancer research : an official journal of the American Association for Cancer Research
Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer. Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression. These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors. .
10.1158/1078-0432.CCR-16-3186
Local surgical, ablative, and radiation treatment of metastases.
Timmerman Robert D,Bizekis Costas S,Pass Harvey I,Fong Yuman,Dupuy Damian E,Dawson Laura A,Lu David
CA: a cancer journal for clinicians
Because local therapies directed toward a specific tumor mass are known to be effective for treating early-stage cancers, it should be no surprise that there has been considerable historical experience using local therapies for metastatic disease. In more recent years, increasing interest in the use of local therapy for metastases likely has arisen from improvements in systemic therapy. In the absence of effective systemic therapies, such local treatments were often considered futile given both the difficulty in eliminating all sites of identifiable metastatic disease as well as realities regarding the rapid natural history of uncontrolled tumor dissemination. However, with a higher likelihood of patients surviving longer after effective systemic therapy, even if not cured, the goal of the eradication of residual metastases via potent local therapies can be rationalized. However, this rationalization should be evidence-based so as to avoid harming patients for no established benefit. Although surgical metastectomy remains the most common and first-line standard among local therapies, nonsurgical alternatives, including thermal ablation and stereotactic body radiotherapy, have become increasingly popular because they are generally less invasive than surgery and have demonstrated considerable promise in eradicating macroscopic tumor. Rather than eliminating the need for local therapies, improvements in systemic therapies appear to be increasing the prudent utilization of modern local therapies in patients presenting with more advanced cancer.
10.3322/caac.20013
Clinical significance of defective dendritic cell differentiation in cancer.
Almand B,Resser J R,Lindman B,Nadaf S,Clark J I,Kwon E D,Carbone D P,Gabrilovich D I
Clinical cancer research : an official journal of the American Association for Cancer Research
Defective dendritic cell (DC) function has been described previously in cancer patients and tumor-bearing mice. It can be an important factor in the escape of tumors from immune system control. However, the mechanism and clinical significance of this phenomenon remain unclear. Here, 93 patients with breast, head and neck, and lung cancer were investigated. The function of peripheral blood and tumor draining lymph node DCs was equally impaired in cancer patients, consistent with a systemic rather than a local effect of tumor on DCs. The number of DCs was dramatically reduced in the peripheral blood of cancer patients. This decrease was associated with the accumulation of cells lacking markers of mature hematopoietic cells. The presence of these immature cells was closely associated with the stage and duration of the disease. Surgical removal of tumor resulted in partial reversal of the observed effects. The presence of immature cells in the peripheral blood of cancer patients was closely associated with an increased plasma level of vascular endothelial growth factor but not interleukin 6, granulocyte macrophage colony-stimulating factor, macrophage colony-stimulating factor, interleukin 10, or transforming growth factor-beta and was decreased in lung cancer patients receiving therapy with antivascular endothelial growth factor antibodies. These data indicate that defective DC function in cancer patients is the result of decreased numbers of competent DCs and the accumulation of immature cells. This effect may have significant clinical implications.
Ets2 anchors the prometastatic function of mutant p53 in osteosarcoma.
Liu Daniel D,Kang Yibin
Genes & development
Mutations in the tumor suppressor p53 occur in a majority of human cancers. Some gain-of-function (GOF) p53 mutations endow tumor cells with increased metastatic ability, although our understanding of the underlying mechanism remains incomplete. In this issue of , Pourebrahim and colleagues (pp. 1847-1857) develop a new mouse model of osteosarcoma in which a GOF mutant p53 allele is expressed specifically in osteoblasts, while the tumor microenvironment remains wild type for p53, allowing for the study of cell-autonomous functions. In this model, the role of GOF mutant p53 in promoting lung metastasis is shown to be critically dependent on the transcription factor Ets2 and is accompanied by the elevated expression of a cluster of small nucleolar RNAs (snoRNAs).
10.1101/gad.307439.117
TP53 in bone and soft tissue sarcomas.
Thoenen Elizabeth,Curl Amanda,Iwakuma Tomoo
Pharmacology & therapeutics
Genomic and functional study of existing and emerging sarcoma targets, such as fusion proteins, chromosomal aberrations, reduced tumor suppressor activity, and oncogenic drivers, is broadening our understanding of sarcomagenesis. Among these mechanisms, the tumor suppressor p53 (TP53) plays significant roles in the suppression of bone and soft tissue sarcoma progression. Although mutations in TP53 were thought to be relatively low in sarcomas, modern techniques including whole-genome sequencing have recently illuminated unappreciated alterations in TP53 in osteosarcoma. In addition, oncogenic gain-of-function activities of missense mutant p53 (mutp53) have been reported in sarcomas. Moreover, new targeting strategies for TP53 have been discovered: restoration of wild-type p53 (wtp53) activity through inhibition of TP53 negative regulators, reactivation of the wtp53 activity from mutp53, depletion of mutp53, and targeting of vulnerabilities in cells with TP53 deletions or mutations. These discoveries enable development of novel therapeutic strategies for therapy-resistant sarcomas. We have outlined nine bone and soft tissue sarcomas for which TP53 plays a crucial tumor suppressive role. These include osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma (RMS), leiomyosarcoma (LMS), synovial sarcoma, liposarcoma (LPS), angiosarcoma, and undifferentiated pleomorphic sarcoma (UPS).
10.1016/j.pharmthera.2019.06.010
A role for maintenance therapy in managing sarcoma.
Ray-Coquard Isabelle,Le Cesne Axel
Cancer treatment reviews
Despite the use of recommended chemotherapy regimens, patients with metastatic sarcomas have a poor prognosis. To date, the median overall survival for metastatic disease remains less than 18 months. First-line treatment of most metastatic sarcomas consists of chemotherapy with or without surgical excision of residual disease, followed by "watchful waiting" until disease progression or recurrence. According to the current treatment paradigm, recommended by United States and European clinical guidelines, chemotherapy is administered for a fixed number of cycles, and then a watchful waiting approach is taken once a best response is achieved. Single-agent doxorubicin remains the standard for treatment of most soft-tissue sarcomas (STS), as combination and dose-intense regimens have largely failed to improve survival. Combination chemotherapy is the standard treatment approach for osteosarcoma and Ewing's sarcoma, but outcomes are poor for patients with recurrent disease. In order to improve outcomes (in particular, progression-free survival [PFS] and overall survival [OS]), strategies shown to be effective in other solid malignancies, such as maintenance therapy and long-term treatment with targeted therapy, are being investigated in patients with advanced sarcomas. One potential promising approach is the use of mammalian target of rapamycin (mTOR) inhibitors for maintenance therapy. One such mTOR inhibitor, ridaforolimus (AP23573, MK-8669), is currently being evaluated in patients with advanced bone and STS in the ongoing Sarcoma mUlti-Center Clinical Evaluation of the Efficacy of riDaforolimus (SUCCEED) trial.
10.1016/j.ctrv.2011.07.003
New targets and approaches in osteosarcoma.
Gill Jonathan,Ahluwalia Manpreet K,Geller David,Gorlick Richard
Pharmacology & therapeutics
Osteosarcoma is the most common primary tumor of bone. Approximately 2/3 of patients who present with localized osteosarcoma can be expected to be cured of their disease with surgery and routine chemotherapy. Only 1/3 of patients with metastases detectable at presentation will be cured. These survival trends have stagnated over the past 20 years using conventional chemotherapy. New agents need to be rationally investigated to strive for improvement in the survival of patients diagnosed with osteosarcoma. This manuscript will review the rationale for conventional chemotherapy used in the treatment of osteosarcoma, as well as agents in varying stages of development that may have promise for treatment in the future.
10.1016/j.pharmthera.2012.09.003
Osteosarcoma treatment - where do we stand? A state of the art review.
Luetke Anja,Meyers Paul A,Lewis Ian,Juergens Heribert
Cancer treatment reviews
Long-term outcome for patients with high-grade osteosarcoma has improved with the addition of systemic chemotherapy, but subsequent progress has been less marked. Modern, multiagent, dose-intensive chemotherapy in conjunction with surgery achieves a 5-year event-free survival of 60-70% in extremity localized, non-metastatic disease. A major, as yet unsolved, problem is the poor prognosis for metastatic relapse or recurrence, and for patients with axial disease. This article reviews the current state of the art of systemic osteosarcoma therapy by focusing on the experiences of cooperative osteosarcoma groups. Also, we shed light on questions and challenges posed by the aggressiveness of the tumor, and we consider potential future directions that may be critical to progress in the prognosis of high-grade osteosarcoma.
10.1016/j.ctrv.2013.11.006
Local Control of Soft Tissue and Bone Sarcomas.
Crompton Joseph G,Ogura Koichi,Bernthal Nicholas M,Kawai Akira,Eilber Fritz C
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Sarcomas of soft tissue and bone are mesenchymal malignancies that can arise in any anatomic location, most commonly the extremity, retroperitoneum, and trunk. Even for lower grade histologic subtypes, local recurrence can cause significant morbidity and even disease-related death. Although surgery remains the cornerstone of local control, perioperative radiation and systemic therapy are often important adjuvants. This review will summarize the current therapeutic approaches for local control of soft tissue and bone sarcomas.
10.1200/JCO.2017.75.2717
Osteosarcoma.
Ritter J,Bielack S S
Annals of oncology : official journal of the European Society for Medical Oncology
The successful treatment of patients with osteosarcoma requires close cooperation within an experienced multidisciplinary team including pediatric or medical oncologists, surgeons, pathologists and radiologists. Therefore, therapy should be performed in specialized centers able to provide access to the full spectrum of care. As in other rare malignancies, treatment should be administered within prospective multicenter trials. Therapy must include complete surgical removal of all detectable tumor sites as well as multiagent chemotherapy. The chemotherapy regimen should include several or all of the following four drugs: doxorubicin, high-dose methotrexate with leukovorin-rescue, cisplatin and ifosfamide. Preoperative (neoadjuvant) plus postoperative (adjuvant) polychemotherapy should be preferred, because it allows preparation for safe surgery and preparation of the appropriate prosthesis for the individual patient. The choice of the postponed definitive surgical procedure should be influenced by the anatomical site of the primary tumor, its relationship to neighboring structures, such as vessels and nerves, age and growth potential of the patient, and probably also by the response of the tumor to preoperative chemotherapy. A major, as yet unsolved, problem is the dismal prognosis for patients with unresectable or relapsed osteosarcomas. Novel approaches are needed in order to improve their prognosis.
10.1093/annonc/mdq276
Sequelae of osteosarcoma medical therapy: a review of rare acute toxicities and late effects.
Janeway Katherine A,Grier Holcombe E
The Lancet. Oncology
Since the introduction of multi-agent chemotherapy for osteosarcoma over 30 years ago, overall survival has exceeded 50%. A clear understanding of the acute complications and late effects of osteosarcoma therapy is required to care effectively for patients with osteosarcoma undergoing active treatment, and for the increasing number of osteosarcoma survivors. There has now been sufficient cumulative experience treating patients with osteosarcoma with active anti-osteosarcoma chemotherapy agents, high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide to recognise and understand rare toxicities associated with these agents, and to identify the late effects of osteosarcoma therapy. Late effects and rare toxicities of osteosarcoma include cardiac toxicity, acute and chronic nephrotoxicity, neurotoxicity, hearing loss, infertility, and second malignant neoplasms. Reducing the complications of osteosarcoma therapy is an important goal that will require the identification of clear prognostic indicators, the development of biologically-based therapies, and improved antidotes for the active anti-osteosarcoma cytotoxic drugs.
10.1016/S1470-2045(10)70062-0
Translational biology of osteosarcoma.
Kansara Maya,Teng Michele W,Smyth Mark J,Thomas David M
Nature reviews. Cancer
For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.
10.1038/nrc3838
Osteosarcoma: Current Treatment and a Collaborative Pathway to Success.
Isakoff Michael S,Bielack Stefan S,Meltzer Paul,Gorlick Richard
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor.
10.1200/JCO.2014.59.4895
Osteosarcoma, Chondrosarcoma, and Chordoma.
Whelan Jeremy S,Davis Lara E
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Osteosarcoma (OS), chondrosarcoma, and chordoma are characterized by multiple challenges to the investigator, clinician, and patient. One consequence of their rarity among sarcomas, as well as their biologic and clinical heterogeneity, is that management guidelines are inadequate to inform the range of individual patient-treatment decisions from diagnosis, approaches to surgery, chemotherapy, radiotherapy, treatment of recurrence, palliative care, and quality of survivorship. Of high-grade sarcomas, OSs are among the most curable, with more than two-thirds of patients with localized disease likely to achieve long-term survival. Neoadjuvant chemotherapy comprising cisplatin, doxorubicin, and methotrexate with intercalated surgery is the standard of care for resectable OS in those younger than 40 years. Outcomes for OS presenting with unresectable metastases or recurrent disease, or in those older than 40 years are generally poor. Overall results have improved little for all patients with OS, and new treatments are needed. Surgical resection remains the cornerstone of management for chondrosarcoma and chordoma. However, the application of new biologic insights to therapeutic development indicates that improved treatments may soon be routine for patients with chondrosarcoma and chordoma for whom surgery alone is inadequate. For all these uncommon diseases, patients should be offered specialist expert care delivered by experienced multidisciplinary teams in high-volume centers.
10.1200/JCO.2017.75.1743
Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy.
Gianferante D Matthew,Mirabello Lisa,Savage Sharon A
Nature reviews. Endocrinology
Clinical outcomes and treatment modalities for osteosarcoma, the most common primary cancer of bone, have changed very little over the past 30 years. The peak incidence of osteosarcoma occurs during the adolescent growth spurt, which suggests that bone growth and pubertal hormones are important in the aetiology of the disease. Tall stature, high birth weight and certain inherited cancer predisposition syndromes are well-described risk factors for osteosarcoma. Common genetic variants are also associated with osteosarcoma. The somatic genome of osteosarcoma is highly aneuploid, exhibits extensive intratumoural heterogeneity and has a higher mutation rate than most other paediatric cancers. Complex pathways related to bone growth and development and tumorigenesis are also important in osteosarcoma biology. In this Review, we discuss the contributions of germline and somatic genetics, tumour biology and animal models in improving our understanding of osteosarcoma aetiology, and their potential to identify novel therapeutic targets and thus improve the lives of patients with osteosarcoma.
10.1038/nrendo.2017.16