Therapy For Sarcoma Research Articles

Abstract 4607: Targeted nanoparticle delivery of irinotecan and Ewing sarcoma-specific siRNA is an effective combination therapy for Ewing sarcoma

Abstract Background: Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor affecting children and adolescents with an overall survival rate of 50%. Irinotecan (IR) is an effective chemotherapeutic agent but is associated with significant toxicity. Using an anti-CD99 targeted hybrid polymerized lipid nanoparticle containing IR, NV103, in pre-clinical mouse xenograft model of the disease, tumor ablation was achieved at 2mg/kg of IR versus 50mg/kg for free IR. All ES harbor a chromosomal translocation resulting in expression of a fusion EWS-FLI1 protein or equivalent. This chimeric gene is a transcriptional regulator that upregulates the FEZF1 and FEZF1-AS1 genes. Both EWS-FLI1 and FEZF1-AS1 genes are unique to ES and are not expressed in normal adult tissues. EWS-FLI1 promotes cell growth while the FEZF1-AS1 complex promotes tumor metastasis, a hallmark of ES. In vitro RNAi targeting of EF and FEZF1-AS1 results in tumor cell death. We hypothesized that combining EWS-FLI1 and/or FEZF1-AS1 targeted RNAi therapy with NV103 cytotoxic therapy would be more effective than any single modality therapy. Methods: NV103 was provided by NanoValent Pharmaceuticals. siRNA containing lipid nanoparticles (LNP-siRNA) were generated using PreciGenome NanoGenerator. siRNA was quantified using the ribogreen assay. Nanoparticles were analyzed for size and particle numbers by NanoSight. siRNA was used to target the following genes- EWS-FLI1, FEZF1, FEZF1-AS1, or GFP. A673 cells expressing GFP were used for this in vitro study. Various doses of IR and siRNA were used in combination and cell growth/death was imaged live using Incucyte. ATP assay was used to confirm live cells and to determine minimum effective dose (MED) over 72 hours of treatment. Results: LNP-siRNA, mean diameter 70nm and PDI<0.2, encapsulated 90% of the siRNA in solution. LNP are stable at 4°C for at least 4 weeks with minimal-to-no loss of activity. NV103 had a MED of 1µM. MED of various siRNA was 30 to 50nM. Combination of NV103 and LNP-siRNA reduced MED of IR to 250nM. One treatment dose of LNP-siRNA followed by NV103 treatment three days later maintained significant cell death over 10 days post treatment initiation. Control cells were 97% more confluent than NV103/EWS-FLI1 siRNA treated ones, 85% more than NV103/FEZF1 siRNA cells and 92% more than NV103/FEZF1-AS1 treated cells. siRNA combinations of EWS-FLI1 and FEZF1 or FEZF1-AS1 along with NV103 added no further benefit. Conclusion: Combination nanoparticle therapy of IR and ES-specific siRNA reduces IR MED by four-fold. LNP delivery of siRNA enables tumor-specific gene targeting. Most have no available small molecule therapy. Targeting ES cells with both a low dose (250nM) of IR and 30-50nM of siRNA against unique tumor biomarkers results in increased cell death with no IR toxicity. Further animal studies are required to determine the effectiveness of such therapy in vivo. Citation Format: Sheetal A. Mitra, Jean-Hugues Parmentier, Hyung-Gyoo Kang, Timothy J. Triche. Targeted nanoparticle delivery of irinotecan and Ewing sarcoma-specific siRNA is an effective combination therapy for Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4607.

Abstract 7259: Effectiveness and comparison of CAR-T cell therapies for synovial sarcoma; HER2-targeted CAR-T and NKG2D-based CAR-T

Abstract Introduction: In Japan since 2019, CAR-T cell therapy has been used to treat patients with relapsed or refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma and has shown excellent clinical results. Clinical studies of CAR-T cell therapies targeting various antigens, such as HER2, have been conducted, but the therapeutic outcome in sarcoma is still limited. We have previously reported that HER2-targeted CAR-T cells show antitumor effects for synovial sarcoma in vitro. The purpose of this study is to compare HER2-targeted CAR-T cells and NKG2D-based CAR-T cells in antitumor effect and specific responses for synovial sarcoma in vitro. Materials and Methods: Surface expressions of HER2 and NKG2D ligands on three synovial sarcoma cell lines were detected by using recombinant human HER2 Fc chimeric protein and that of NKG2D, followed by staining with PE-conjugated anti-human IgG secondary antibody. We generated 4-1BB-type second generation CAR-T cells targeting NKG2D ligands and examined their antitumor effects and specific responses against synovial sarcoma cells. In addition, we compared the differences between HER2-targeted CAR-T cells and NKG2D-based CAR-T cells by co-culturing with synovial sarcoma cells using short-term assay (WST-8 assay), long-term assay (Real-time Cell Analysis) and CD107a assay. Results: HER2 and NKG2D ligands were found to be expressed by flow cytometry in three synovial sarcoma cell lines. In vitro, NKG2D-based CAR-T cells showed antitumor effects against synovial sarcoma cells, including degranulation and cytokine production. Furthermore, NKG2D-based CAR-T cells showed stronger antitumor effects than HER2-targeted CAR-T cells in both short- and long-term assays and expressed higher levels of CD107a. Conclusions: In this study, NKG2D-based CAR-T cells showed more antitumor effects than HER2-targeted CAR-T cells in vitro. Although the reason for this is not clear, we hypothesize that NKG2D ligands may be induced in synovial sarcoma cells by co-culture with CAR-T cells because HER2 is a cancer-specific antigen, whereas NKG2D ligands are ligands for activating receptors of natural killer cells. Further studies, including in vivo studies, will be conducted to verify the difference in anti-tumor effects between these CAR-T cells. Citation Format: Tomohiro Miyazaki, Chihaya Imai, Naoki Oike, Yudai Murayama, Takashi Ariizumi, Minori Baba, Yasushi Kasahara, Hiroyuki Kawashima. Effectiveness and comparison of CAR-T cell therapies for synovial sarcoma; HER2-targeted CAR-T and NKG2D-based CAR-T [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7259.

Abstract 1096: Enhancing effector function in T cell adoptive cell therapy in murine models of pediatric sarcomas

Abstract New treatment approaches for high-risk pediatric sarcomas are desperately needed. Immunotherapy advances with adoptive cell therapy in hematologic malignancies have not yet translated to pediatric solid tumors including sarcomas. Hallmarks of the immune microenvironment in pediatric sarcomas include the presence of immunosuppressive cytokines and immune cells and a lack of potent T cell activation. We are seeking ways to overcome these barriers to effective adoptive cell therapy in pediatric sarcoma. We are exploring introduction of a novel synthetic co-receptor, CD8a:MyD88, that can augment tumor-specific T cell effector function and potentially improve outcomes in murine models of sarcoma. Tumor-antigen specific T cells or tumor-infiltrating T cell populations are transduced ex vivo to express the CD8a:MyD88 synthetic co-receptor resulting in MyD88 signaling when T cells encounter their cognate MHC I/epitope complex. We have studied the effects of CD8a:MyD88 expression on cytokine production and lytic activity against murine sarcoma cell lines in vitro. Initial experiments utilized the OT1 T cell model (specific to the model antigen chicken ovalbumin) which we introduced into our murine sarcoma cell lines (KPSarc pleomorphic sarcoma and M3-9M rhabdomyosarcoma). Using GFP as a marker of T cell transduction, the production of effector cytokine interferon gamma was measured following T cell activation compared with GFP-negative non-transduced T cells. CD8a:MyD88 expressing T cells expressed higher levels of interferon gamma at basal levels and following antigen-specific activation when co-cultured with Ova-expressing sarcoma cells. Improved tumor-specific lytic function in CD8a:MyD88 expressing T cells was also observed in co-culture experiments compared to untransduced or control vector- transduced T cells. We further hypothesized that skewing T cell differentiation toward an effector phenotype with the addition of interleukin-12 during T cell expansion would increase the anti-tumor effect of the CD8a:MyD88 expressing T cells. Co-culture with our murine sarcoma cell lines showed increased tumor-lytic function in T cells primed with IL-12. We have ongoing experiments studying the in vivo effects of the CD8a:MyD88 expressing T cells in model antigen-expressing murine sarcoma models. In addition, the ability of the CD8a:MyD88 co-receptor to augment the effector function of polyclonal sarcoma infiltrating T cells is being explored. These results will further define the obstacles and potential solutions to successful adoptive T cell therapy for pediatric sarcomas. Citation Format: Jessica P. Sanchez, Eduardo Davila, Brian H. Ladle. Enhancing effector function in T cell adoptive cell therapy in murine models of pediatric sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1096.

Intraoperative radiation therapy for pediatric sarcomas and other solid tumors.

To evaluate local failure (LF) and toxicity after intraoperative radiation therapy (IORT) in pediatric solid tumors (ST). A single-institution retrospective study of 96 pediatric patients (108 applications) with ST treated from 1995 to 2022 with IORT. LF was calculated via cumulative incidence function and overall survival (OS) by Kaplan-Meier method, both from the day of surgery. Median age at time of IORT was 8years (range: 0.8-20.9years). Median follow-up for all patients and surviving patients was 16months and 3years, respectively. The most common histologies included rhabdomyosarcoma (n=42), Ewing sarcoma (n=10), and Wilms tumor (n=9). Most (95%) received chemotherapy, 37% had prior external beam radiation therapy to the site of IORT, and 46% had a prior surgery for tumor resection. About half (54%) were treated with upfront IORT to the primary tumor due to difficult circumstances such as very young age or challenging anatomy. The median IORT dose was 12Gy (range: 4-18Gy), and median area treated was 24cm2 (range: 2-198cm2). The cumulative incidence of LF was 17% at 2years and 23% at 5years. Toxicity from IORT was reasonable, with postoperative complications likely related to IORT seen in 15 (16%) patients. Our study represents the largest and most recent analysis of efficacy and safety of IORT in pediatric patients with ST. Less than one quarter of all patients failed locally with acceptable toxicities. Overall, IORT is an effective and safe technique to achieve local control in patients with challenging circumstances.

Abstract 6642: Exploring the x-ray psoralen activated cancer therapy mechanism of action in a genetically engineered mouse model of soft tissue sarcoma

Abstract BACKGROUND: Psoralen is a natural ultraviolet activated compound that has been used for over 70 years to treat skin cancer, psoriasis, and vitiligo. Recently, to expand its use beyond external treatment, a novel therapeutic called X-PACT (X-ray psoralen activated cancer therapy) was created to treat internal tumors. A combination of 8-methoxypsoralen and phosphors that convert low doses of x-ray radiation to ultraviolet (UV) light are injected into solid tumors and subsequently activated by x-ray photons with considerable antineoplastic effect. Notably, canine clinical trials have observed significant abscopal effects of X-PACT therapy on metastatic lesions throughout patients, but the immunomodulatory mechanisms of action are unclear (Nolan et al, in submission). Here, we present preliminary data investigating the immune response to X-PACT therapy in a murine soft tissue sarcoma (STS) model. METHODS: Six mice of the inducible KrasG12D/+; p53flox/flox (KP) murine STS model with palpable, gastrocnemius tumors were used in this initial study. Four mice underwent treatment with X-PACT. In this group, psoralen was mixed with energy converters and injected into the tumor. The mice then received low-level radiation to activate the drug. Treatment was performed five times over a 15-day period and the animals were sacrificed within 48 hours of final treatment. The other two mice with induced tumors received no treatment prior to sacrifice. For both groups, a cardiac blood draw was performed at the time of sacrifice to obtain plasma serum for analysis. Luminex xMAP technology was used for multiplexed quantification of 45 mouse cytokines, chemokines and growth factors. RESULTS: There were five markers that showed significantly different levels between the treated and control groups. Results indicated significantly higher (p = 0.006) plasma concentrations of macrophage derived chemokine (MDC) following five rounds of treatment with X-PACT therapy. Additionally, the treated mice displayed significantly lower concentrations of granulocyte colony-stimulating factor (G-CSF, p = 0.003), eotaxin (p = 0.016), tissue inhibitor of matrix metalloproteinase 1 (TIMP1, p = 0.024), and interleukin-1β (IL-1β, p = 0.033) compared to untreated mice with STS. CONCLUSION: In humans, MDC levels are associated with longer survival and lower cancer severity. G-CSF, eotaxin, TIMP1, and IL-1β are upregulated in cancer patients and correlate with disease severity. Together, the lower concentrations of G-CSF, Eotaxin, TIMP1, and IL-1β suggest a softening of cancer severity following X-PACT treatment. Further studies and larger sample sizes are necessary to confirm and expand upon these preliminary findings. Citation Format: Beatrice Schleupner, Alexandra Hunter Aitchison, Elle MacAlpine, Nicole Cantor, Jason Somarelli, Brian Brigman, Julia Visgauss, Michael Monument, William Eward. Exploring the x-ray psoralen activated cancer therapy mechanism of action in a genetically engineered mouse model of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6642.

Radiation therapy for retroperitoneal sarcoma: practice patterns in North America

BackgroundThe addition of radiation therapy (RT) to surgery in retroperitoneal sarcoma (RPS) remains controversial. We examined practice patterns in the use of RT for patients with RPS over time in a large, national cohort.MethodsPatients in the National Cancer Database (2004–2017) who underwent resection of RPS were included. Trends over time for proportions were calculated using contingency tables with Cochran-Armitage Trend test.ResultsOf 7,485 patients who underwent resection, 1,821 (24.3%) received RT (adjuvant: 59.9%, neoadjuvant: 40.1%). The use of RT decreased annually by < 1% (p = 0.0178). There was an average annual increase of neoadjuvant RT by 13% compared to an average annual decrease of adjuvant RT by 6% (p < 0.0001). Treatment at high-volume centers (OR 14.795, p < 0.0001) and tumor > 10 cm (OR 2.009, p = 0.001) were associated with neoadjuvant RT. In contrast liposarcomas (OR 0.574, p = 0.001) were associated with adjuvant RT. There was no statistically significant difference in overall survival between patients treated with surgery alone versus surgery and RT (p = 0.07).ConclusionIn the United States, the use of RT for RPS has decreased over time, with a shift towards neoadjuvant RT. However, a large percentage of patients are still receiving adjuvant RT and this mostly occurs at low-volume hospitals.

P 06 - Multi-institutional experience of pre-operative proton therapy for retroperitoneal sarcoma in the prospective Proton Collaborative Group (PCG) Registry

P 06 - Multi-institutional experience of pre-operative proton therapy for retroperitoneal sarcoma in the prospective Proton Collaborative Group (PCG) Registry

The Effect of Photodynamic Therapy Using 5-Aminolevulinic Acid in Bone and Soft Tissue Sarcoma Cells.

5-Aminolevulinic acid (5-ALA) is a natural amino acid and a precursor of protoporphyrin IX (PpIX). Following light irradiation, the PpIX generates reactive oxygen species (ROS) in the presence of oxygen. Increased ROS levels can cause apoptotic cell death and necrosis of targeted cancer cells. This study examined whether photodynamic therapy using 5ALA (5-ALA PDT) could be used as a potential adjuvant therapy for bone and soft tissue sarcomas. The human osteosarcoma (143B), mouse osteosarcoma (LM8), human fibrosarcoma cell (HT1080) cell lines were used. In vitro, cultured cells were exposed to 5-ALA at various concentrations followed by strobe scope light irradiation for 10 min as 5-ALA PDT. Cell viability was then measured. In vivo, each tumor cell line was inoculated subcutaneously into the backs of mice. In the 5-ALA PDT group, 5-ALA (250 mg/kg) was administered intraperitoneally followed by light irradiation. Change in tumor volume by 5-ALA PDT were primarily evaluated. In vitro, treatment of sarcoma cells with 100 and 200 μg/ml 5-ALA PDT significantly inhibited cell proliferation at 24 and 48 h compared with the group treated with 0 and 10 μg/ml 5-ALA PDT. In vivo, in all cell lines, a significant inhibition of the tumor volume was observed in the 5-ALA-PDT group as compared to that in control, strobe scope light, and 5-ALA groups. 5-ALA PDT effectively inhibited proliferation of bone and soft tissue sarcoma cell lines. Further in vivo research using other subtypes of bone and soft tissue sarcoma is warranted to confirm the applicability in the clinical setting.

Acute Lymphoblastic Leukemia (ALL) as a secondary malignancy in adolescent patient after completion of Ewing's sarcoma chemotherapy: a case report

OBJECTIVE: To report an adolescent patient who was diagnosed with Acute lymphoblastic leukemia (ALL) after completing Ewing sarcoma (ES) therapy. CASE: A 14 years old girl complained of left crusis tumor since 4 months before hospitalized. Tumor biopsy showed a round cell tumor, as well as immunohistochemistry which showed a positive CD99, consistent with ES. The patient had received 14 cycles chemotherapy for 7 months with regimens vincristine 1.5 mg/m2, cyclophosfamide 1200 mg/m2, dactinomycin 0.5 mg/m2, and doxorubicin 30 mg/m2. Between chemotherapy, patient also was given granulocyte colony-stimulating factor several times. Pasien also undergo 31 times radiation therapy with total 31x1.8 Gy (55.8 Gy). Two months after last chemotherapy for Ewing sarcoma, she was admitted again with prolonged fever, and pallor.Laboratorium showed leukocytosis (88.86x103uL), monocytosis (41%), severe neutropenia (0.39x103uL), severe normochromic normocytic anemia (4,3 g/dL), severe thrombocytopenia (4x103uL), reticulocytopenia (0,46%), with lymphoblast in peripheral blood smear. Bone marrow aspiration result showed lymphoblast infiltration 60% with heterogen morphology, no cluster cell non hematopoetic in bone marrow, consisten with acute lymphoblastic leukemia (ALL-L2) suspected secondary malignancy from Ewing’s Sarcoma. Patient underwent chemotherapy for high risk ALL at induction phase with combination of vincristin, daunorubicin, L-asparginase, metotrexate high dose, prednison, and 6-mercaptopurine. After completing induction phase, the patient’s condition get worsening and later died. CONCLUSION: ES survivors are at significant risk for secondary malignancies. Leukimia is one of which the most common secondary malignancies. Young children are particularly susceptible to the mutagenic effects of both chemotherapy and radiotherapy, as proven by several studies.

Predicting prognosis and immune status in sarcomas by identifying necroptosis-related lncRNAs.

Sarcomas are a type of highly heterogeneous malignant tumors originating from mesenchymal tissues. Necroptosis is intricately connected to the oncogenesis and progression of tumors. The main goal of this research is to assess the prognostic value of necroptosis-related lncRNAs (NRlncRNAs) in sarcomas and to develop a risk model based on NRlncRNAs to evaluate prognostic and immune status of the sarcomas. We screened NRlncRNAs using the gene co-expression network, developed a prognostic risk model of sarcomas, and then verified the model. Following that, various bioinformatics analysis algorithms were employed to analyze the distinct characteristics of patients of the risk model. Furthermore, the function and regulatory mechanism of NRlncRNA SNHG6 in sarcomas were investigated through osteosarcoma cell experiments, such as qRT-PCR, Western blot, CCK-8, clone formation, and transwell assay. We successfully developed a NRlncRNAs-related prognostic risk model and screened 5 prognosis-related NRlncRNAs, with SNGH6 being the most significant for prognosis of patients. According to results, the significant differences exist in prognosis, clinical characteristics, and tumor immune status among patients of the risk model. The experiments of osteosarcoma cells demonstrated that NRlncRNA SNHG6 knockdown significantly attenuated the cells' proliferation, migration, and invasion. qRT-PCR and WB results showed that SNHG6 regulated AXL and AKT signaling. We have developed an innovative investigation on NRlncRNAs, which can serve as a reference for diagnosis, therapy, and prognosis of sarcomas. Additionally, we demonstrated that NRlncRNA SNHG6 regulated AXL and AKT signaling in osteosarcoma cells and the proliferation, migration, and invasion of tumor cells.

Efficacy of vincristine as a rescue therapy for canine histiocytic sarcoma.

Canine histiocytic sarcoma (CHS) is a malignant tumor derived from macrophages and dendritic cells. Since effective chemotherapy is needed for CHS cases, we conducted this prospective study to evaluate the efficacy and adverse events of vincristine treatment as a rescue therapy for this disease. We administered vincristine to nine CHS cases that acquired resistance to lomustine or nimustine. Complete remission was achieved in one dog, partial remission in two dogs, stable disease in five dogs, and progressive disease in one dog. The median progression-free survival was 21 days (range: 7-71 days). Severe adverse effect was observed in one dog (Grade 3 thrombocytopenia). It is essential to establish novel effective treatments for CHS.

Dose-Escalated Preoperative Proton Therapy for Retroperitoneal Sarcomas: Initial Outcomes of a New Treatment Paradigm

Retroperitoneal sarcomas (RPS) have varied treatment practices with regard to the use of radiation therapy (RT). Preoperative RT ∼50 Gy is commonly used, but the Surgery With or Without Radiation Therapy in Untreated Nonmetastatic Retroperitoneal Sarcoma (STRASS-1) randomized trial demonstrated no improvement in abdominal recurrence-free survival with preoperative RT. Dose escalation has been proposed to improve the efficacy of preoperative RT. We analyzed RPS treated with preoperative intensity modulated proton therapy (IMPT) to an escalated dose of 63 Gy at a single institution. Patients who received preoperative RT with IMPT with RPS between January 2015 and October 2021 were reviewed. IMPT 63 Gy in 28 fractions to the clinical target volume high-risk and 50.4 Gy in 28 fractions to clinical target volume low-risk was used. Patient baseline characteristics, RT dose parameters, toxicities, margin status, and recurrence patterns were recorded. Local control was computed by Fine-Gray analysis and overall survival by Kaplan-Meier analysis. Sixteen patients met the study criteria (n = 16): 12 primary and 4 isolated local recurrences. Median age was 62 years (IQR, 43.5-66 years) and 62.5% were male; 10 were liposarcoma. The median maximum tumor diameter was 19.9 cm (IQR, 12-24 cm). With a median follow-up of 18 months (IQR, 11.5-37 months), the estimated 3-year freedom from local failure rate was 68.2% (95% CI, 41.7%-94.7%); 3-year overall survival (OS) rate was 68.8% (95% CI, 41.9%-95.8%). No Radiation Therapy Oncology Group grade ≥3 acute or late toxicities were noted. In our RPS cohort, preoperative dose-escalated RT to 63 Gy demonstrated comparable local control without G3 acute toxicities. Given the high local recurrence rates of RPS, this approach warrants further study to validate these results and identify patients most likely to benefit from therapy.

Neoadjuvant Therapies Do Not Reduce Epidermal Growth Factor Receptor (EGFR) Expression or EGFR-Targeted Fluorescence in a Murine Model of Soft-Tissue Sarcomas.

ABY-029, an epidermal growth factor receptor (EGFR)-targeted, synthetic Affibody peptide labeled with a near-infrared fluorophore, is under investigation for fluorescence-guided surgery of sarcomas. To date, studies using ABY-029 have occurred in tumors naïve to chemotherapy (CTx) and radiation therapy (RTx), although these neoadjuvant therapies are frequently used for sarcoma treatment in humans. The goal of this study was to evaluate the impact of CTx and RTx on tumor EGFR expression and ABY-029 fluorescence of human soft-tissue sarcoma xenografts in a murine model. Immunodeficient mice (n = 98) were divided into five sarcoma xenograft groups and three treatment groups - CTx only, RTx only, and CTx followed by RTx, plus controls. Four hours post-injection of ABY-029, animals were sacrificed followed by immediate fluorescence imaging of ex vivo adipose, muscle, nerve, and tumor tissues. Histological hematoxylin and eosin staining confirmed tumor type, and immunohistochemistry staining determined EGFR, cluster of differentiation 31 (CD31), and smooth muscle actin (SMA) expression levels. Correlation analysis (Pearson's correlation coefficients, r) and linear regression (unstandardized coefficient estimates, B) were used to determine statistical relationships in molecular expression and tissue fluorescence between xenografts and treatment groups. Neoadjuvant therapies had no broad impact on EGFR expression (|B|≤ 7.0, p ≥ 0.4) or on mean tissue fluorescence (any tissue type, (|B|≤ 2329.0, p ≥ 0.1). Mean tumor fluorescence was significantly related to EGFR expression (r = 0.26, p = 0.01), as expected. Results suggest that ABY-029 as an EGFR-targeted, fluorescent probe is not negatively impacted by neoadjuvant soft-tissue sarcoma therapies, although validation in humans is required.

Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers

Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.

Improved local control following dose-escalated stereotactic ablative radiation therapy (SABR) for metastatic sarcomas: An international multi-institutional experience

BackgroundWe aimed to characterize local control (LC) and overall survival (OS) following stereotactic ablative radiation therapy (SABR) for extracranial sarcoma metastases. MethodsA prospectively-maintained institutional registry was queried for patients with metastases from sarcoma primaries managed with SABR. Kaplan-Meier analysis was utilized for univariate analyses to assess potential prognostic factors regarding LC and OS. A Cox proportional hazards multivariate (MVA) model was employed to further assess initially identified independent variables. ResultsA total of 94 patients with 118 lesions with LC information were identified. Common metastatic sites treated were lung (77), non-spinal bone (15), and spine (10). The median biologically effective dose (BED4) was 175 Gy4 (range56.3 Gy4–360 Gy4) with a median dose/fractionation schedule of 50 Gy/5 fractions. One- and 2-year OS rates were 81.3 % (95 % CI: 71.2–88.1 %6) and 50.5 % (95 % CI: 38.6–61.3 %, respectively. On Cox MVA, advanced age and non-lung metastases were associated with inferior OS (p < 0.03) with patients with 0–2 of these risk factors having estimated 2-year OS of 65.1 %, 38.9 %, and N/A, respectively. One- and 2-year LC rates were 85.3 % (95 % CI: 77.7–90.9 %) and 78.2 % (95 % CI: 67.9–85.6 %), respectively. On MVA, only BED4 < 175 Gy was associated with inferior LC (hazard ratio (HR) = 3.33; p = 0.01). Ten of 118 treated lesions had treatment-related toxicities (all Grade 1–2). ConclusionAge and lung vs. non-lung metastases were prognostic of OS and should be considered in patient selection for SABR. Dose escalation when feasible with BED4 ≥ 175 Gy is recommended given durable LC achieved without a subsequent increase in toxicity.

PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas.

Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas.

Spatially Fractionated Radiation Therapy in Sarcomas: A Large Single-Institution Experience

ObjectiveSpatially fractionated radiation therapy (SFRT) is a recognized technique for enhancing tumor response in radioresistant and bulky tumors. We analyzed clinical and treatment outcomes in patients with bone and soft tissue sarcomas treated with modern SFRT techniques. MethodsPatients with metastatic and/or unresectable sarcoma treated with brass collimator, volumetric modulated arc therapy (VMAT) lattice, or proton SFRT from December 2019-June 2022 were retrospectively reviewed. Consolidative external beam radiation therapy (EBRT) was delivered at the physician's discretion. Patient and treatment characteristics, treatment response (symptom improvement, local control, and imaging response), and toxicity data were collected. ResultsThe cohort consisted of 53 patients treated with 61 SFRT treatments. Median age at treatment was 60.0 years. The primary location was soft tissue in 46 courses (75%) and bone in 15 (25%). Fifty-three courses (87%) were treated for symptom relief. The most utilized SFRT technique was VMAT lattice (n=52, 85%) to a dose of 20 Gy (n=48, 79%, range: 16-20 Gy). EBRT was delivered post-SFRT in 55 (90%) treatment courses with a median time interval from SFRT to EBRT of 5 days (range: 0-14 days). Median physical EBRT dose and fractionation was 40 Gy (range: 9-73.5 Gy) and 10 fractions (range: 3-33 fractions). Median follow up was 7.4 months (range: 0.2-30 months). One-year overall survival and local control rates were 53% and 82%. Symptom relief was documented with 32 treatment courses (60%). Stable or partial response was observed with 47 treatment courses (90%). Four grade 3-4 acute and subacute toxicities were attributable to SFRT (8%). ConclusionsThe current series is the largest to date documenting outcomes for SFRT in sarcomas. Our results suggest combined SFRT with EBRT is associated with a favorable toxicity profile and high rates of symptomatic and radiographic responses for metastatic and/or unresectable sarcomas.

A retrospective study of Kaposi's sarcoma in Hotan region of Xinjiang, China.

Kaposi sarcoma (KS) is the most common cancer in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (AIDS). In 1994, Chang and Moore discovered Kaposi sarcoma associated herpesvirus for the first time in KS lesions in AIDS patients. KS is a low-grade mesenchymal neoplasm of blood and lymphatic vessels that primarily affects the skin, although the disease may become disseminated to the lymphatic system, lungs, airways, or abdominal viscera. In this research, clinical characteristics and treatment of patients of Kaposi sarcoma were retrospectively analyzed in Hotan District, Xinjiang China. We look into the clinical traits, prognosis, and therapy of Kaposi sarcoma. From May 2017 to August 2022, 32 patients were treated in the People's Hospital of Hotan District, Xinjiang Uygur Autonomous Region, China. Twenty-two of these were classic Kaposi sarcomas (cKS), and 10 of these were Kaposi sarcomas linked to AIDS (AIDS-KS). The majority of KS patients were Uyghur. In terms of age at onset, AIDS-KS patients were younger than cKS patients. cKS and AIDS-KS are most frequently manifested in the feet and lower limbs. Ten patients with AIDS-KS have treated with combination antiretroviral therapy (combination antiretroviral therapy) combination chemotherapy, 5 of 10 patients had a complete response, 2 patients achieved partial response, the overall effective rate was 70%, and CD4 + T cells were greater than before. For cKS and AIDS-KS, the median overall survival was 56 and 50.8 months, respectively (P > .05). As a result, antiviral combination chemotherapy can also improve the prognosis of AIDS-KS patients.

1983P Palliative spatially fractionated stereotactic radiation therapy (Lattice) for large sarcoma

1983P Palliative spatially fractionated stereotactic radiation therapy (Lattice) for large sarcoma

Comparison of the Results of Patients Treated With Limb-Sparing Treatment Options in Malignant Bone Tumors: Sharing the Experience of Twelve Bicentric Patients.

Extremity-sparing surgery should be the main objective if a functional extremity is to be obtained in cases of malignant bone tumors. After extensive resection, numerous techniques have been described to reconstruct bone defects. This study aimed to compare the outcomes of patients who underwent external radiation therapy and liquid nitrogen biological reconstruction at two different facilities. The study included 12 patients who received biological reconstruction therapy for bone sarcoma and had at least two years of follow-up. Demographic data, pathological diagnosis, presence of systemic metastasis, and recurrence during follow-up were among the information logged. Patients who used liquid nitrogen were placed in group 1, and those who underwent external irradiation were placed in group 2. After being contacted for their final follow-up appointments, the outcomes were compared by recording the Musculoskeletal Tumor Society Score (MSTSS). For participants with a mean age of 10.75±3.6 (5-17), the follow-up period was 30.2±16.3 months in total. In contrast to the patients in group 1, who experienced union on average after 7.5±1.2 months, those in group 2 experienced union after 7.6±1.1 months. Patients in group 1 had an MSTSS of 75.5±11.8%, while those in group 2 had a score of 77±4.4.There was no discernible difference between the two groups' union times (p>0.05). There was no statistically significant difference between the two groups' MSTSS (p>0.05). After tumor resection, extracorporeal radiation therapyand the application of liquid nitrogen are still useful treatment options and neither of them is superior to the other.