BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we ...conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination ...chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.
Update on Survival in Osteosarcoma Anderson, Megan E., MD
The Orthopedic clinics of North America,
2016, January 2016, 2016-Jan, 2016-01-00, 20160101, Letnik:
47, Številka:
1
Journal Article
Recenzirano
Osteosarcoma is the most common primary bone malignancy in children. Treatment has evolved to include systemic chemotherapy and local control surgery. Although survival improved initially in a ...drastic fashion with this approach, recent decades have seen little to no further gains in this area. Limb salvage surgery evolved with effective chemotherapy and advances in imaging, and continues to improve in the recent era. This article serves as a review of survival in high-grade osteosarcoma: prognostic factors, advances in chemotherapy and surgery, late effects of chemotherapy and surgery in survivors, and future directions.
The role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the ...association between CT/RT with recurrence and survival.
Retrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan–Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed.
370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n = 294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%–62%). Almost half of patients (n = 173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p = 0.50, systemic p = 0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 95% CI 0.26–0.80, p = 0.01).
Although the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS.
•370 patients with localized extremity extraskeletal osteosarcoma (ESOS) treated definitively were evaluated.•There is a significant association between radiotherapy (RT) and decreased local recurrence.•Chemotherapy (CT) did not decrease the risk of systemic recurrence.•Neither CT, nor RT, nor both were associated with improved survival.•Adjuvant therapies in resectable ESOS need careful multidisciplinary discussion.
Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic ...osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.
Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current ...therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.
Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic ...regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding.
Scientific advances have significantly improved our understanding of osteosarcoma, but gaps in our knowledge have impaired our ability to translate new findings into new cures. We present a series of questions that we believe represent the most important and most immediate unsolved problems which, if solved, might change the way we think about and treat this disease.
Osteosarcoma Ritter, J.; Bielack, S. S.
Annals of oncology,
10/2010, Letnik:
21, Številka:
suppl-7
Journal Article
Recenzirano
Odprti dostop
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.
Cancer stem cells in osteosarcoma Brown, Hannah K; Tellez-Gabriel, Marta; Heymann, Dominique
Cancer letters,
02/2017, Letnik:
386
Journal Article
Recenzirano
Odprti dostop
Abstract Osteosarcoma is the most common primary bone tumour in children and adolescents and advanced osteosarcoma patients with evidence of metastasis share a poor prognosis. Osteosarcoma frequently ...gains resistance to standard therapies highlighting the need for improved treatment regimens and identification of novel therapeutic targets. Cancer stem cells (CSC) represent a sub-type of tumour cells attributed to critical steps in cancer including tumour propagation, therapy resistance, recurrence and in some cases metastasis. Recent published work demonstrates evidence of cancer stem cell phenotypes in osteosarcoma with links to drug resistance and tumorigenesis. In this review we will discuss the commonly used isolation techniques for cancer stem cells in osteosarcoma as well as the identified biochemical and molecular markers.
Purpose of Review
Osteosarcoma is mostly seen in bones of children and young adults. When it occurs in older persons, the tumor is considered secondary usually complicating Paget disease or ...irradiated bone. However, there is a second incidence peak of primary osteosarcoma later in life when these tumors occur de novo. This article describes the clinical, imaging, and treatment of POS in older patients, including demographic data of patients from our institution.
Findings
We present our experience with 920 cases of osteosarcoma that were seen between 1984 and 2003 at the University of Texas MD Anderson Cancer Center in Houston, TX, USA. Among the 868 primary osteosarcoma of bones, there were 100 (11.52%), which comprised 69% of the tumors in patients over the age of 50 years. Older patients with primary osteosarcoma tend to have relatively more common axial skeleton involvement, have more distant disease, and are difficult to treat because of concomitant comorbidities. Despite that, most adult patients treated with chemotherapy have shown good results with longer disease-free survival.
Summary
A lytic bone lesion seen in radiographs of elderly patients should include primary osteosarcoma among differential diagnoses. Radical surgery and chemotherapy seem to ensure long-term disease-free survival in most cases. The elderly patients with POS in pelvis, spine, and upper extremities and those with distant disease (metastases) have worse prognosis.
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