Multiple Metastatic Cancer Research Articles

Discovery and Characterization of a Novel Cereblon-Recruiting PRC1 Bridged PROTAC Degrader.

Bridged PROTAC is a novel protein complex degrader strategy that exploits the target protein's binding partner to degrade undruggable proteins by inducing proximity to an E3 ubiquitin ligase. In this study, we discovered for the first time that cereblon (CRBN) can be employed for the bridged PROTAC approach and report the first-in-class CRBN-recruiting and EED-binding polycomb repressive complex 1 (PRC1) degrader, compound 1 (MS181). We show that 1 induces preferential degradation of PRC1 components, BMI1 and RING1B, in an EED-, CRBN-, and ubiquitin-proteosome system (UPS)-dependent manner. Compound 1 also has superior antiproliferative activity in multiple metastatic cancer cell lines over EED-binding PRC2 degraders and can be efficacious in VHL-defective cancer cells. Altogether, compound 1 is a valuable chemical biology tool to study the role of PRC1 in cancer. Importantly, we show that CRBN can be utilized to develop bridged PROTACs, expanding the bridged PROTAC technology for degrading undruggable proteins.

Abstract 4059: Vitokine-2: A TIL-targeting tumor activable engineered IL-2 for cancer treatment

Abstract Background: Interleukin-2 is the first approved immune-oncology (IO) drug to treat multiple metastatic cancers with durable and curative antitumor effects. Yet, its application is restricted due to severe toxicity, short half-life, and a small fraction of response rate. To reduce toxicity and improve efficacy, we developed Vitokine-2, a tumor infiltrating lymphocyte (TIL)-targeting, tumor activable, and precision engineered IL-2 that remains inert systemically but activated in the tumor microenvironment (TME). Methods: Through protein and structure-guided precision engineering, the biological activity of IL-2 was optimized, concealed, guided to exhausted TILs, and activated at TME. The biological activity was determined by measuring proliferation (Ki67) of CD8+ T and NK cells using human peripheral blood mononuclear cells (PBMCs). Pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor efficacy were evaluated in mice, encompassing healthy and multiple syngeneic tumor mouse models. Results: Vitokine-2 was inactive in stimulating CD8+T and NK cell proliferation in vitro. Yet, its biological activity was fully restored following the cleavage and release of the concealing domain. Vitokine-2 displayed a significantly prolonged in vivo pharmacokinetic profile due to half-life extension, concealing and reduction of target sink. Administration of Vitokine-2 in mice resulted in minimal or no detectable activation, proliferation, and expansion of cytotoxic CD8+T and NK cells in the systemic circulation. However, marked CD8+ T cell proliferation and expansion with enhanced expression of granzyme B, a cytotoxic functional biomarker, was observed within the TME. The effect was specific to cytotoxic lymphocytes but not regulatory T cells. Corroborating with the expansion and enhanced functionality of CD8+ T cells in TME, robust antitumor efficacy was observed with Vitokine-2 but not with the non-activable IL-2 counterpart. Furthermore, dose-dependent tumor killing efficacy and complete eradication of tumors were demonstrated in multiple syngeneic tumor models. Vitokine-2 was found to be safe and well tolerated with minimal interferon gamma release and body weight loss even at much higher doses. Conclusion: Vitokine-2 is a TIL-targeting, tumor activable and precision engineered IL-2. It demonstrated robust anti-tumor efficacy with minimal systemic toxicity. It is safe, well tolerated, and permits high dose administration, yielding a widened therapeutic window. Vitokine-2 presents a paradigm-shifting, potentially a first-in-class, highly safe and efficacious IO therapy with an immense potential to address both IO-responsive and unresponsive patient population. Citation Format: Sreerupa V. Challa, Yao-Te Hsieh, Karen Gelinas, Andrea Umana, Wei-chun Weng, Toska Berisha, Cameron Stephens, Yuesheng Li, Jing Xu. Vitokine-2: A TIL-targeting tumor activable engineered IL-2 for cancer treatment [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 4059.

158 Controlling Glioblastoma Invasion In Vivo With CD97

INTRODUCTION: Increased levels of adhesion G Protein-Coupled Receptor (GPCR) CD97 have been detected in multiple metastatic cancers. Glioblastoma (GBM), a Grade-IV Glioma, also overexpress this receptor, and its levels positively correlate with more aggressive GBM invasion. METHODS: CD97 consists of two distinct domains: the large extracellular fragment interacting with ECM and other cell surface receptors and the GPCR core that activates heterotrimeric G Proteins G12/13. To investigate the mechanism of action of CD97, we generated a CD97 knockdown (shCD97) and overexpression (CD97-WT) constructs. Additionally, we generated two functional mutants: a constitutively active mutant lacking the N-Terminus (dNTF) and dominant-negative mutant (H436A) that cannot activate G-Proteins downstream. Glioma Stem Cells (GSC) were transduced by control and CD97 lentiviral constructs and implanted into mouse brains. Once tumors formed the brains were harvested, sliced, and immunostained to evaluate invasion and proliferation. Comparing mutants to control, dunnett’s multiple comparisons test was used for statistical analysis. RESULTS: Similar to CD97-WT, we found that both dNTF and H436A, increase tumor volume (p < 0.05). In contrast, the shCD97 mutant decreased tumor size (p < 0.05). Interestingly, only dNTF significantly increased tumor cell proliferation (p < 0.005), yet CD97-WT and H436A affected proliferation of non-tumor cells in the tumor bulk, indicating that this process requires the N-Terminus Fragment. In addition, over-expression of CD97-WT dramatically increases tumor invasion along myelinated fibers of corpus collosum, and tumor spread in the brain tissue (p < 0.05). Yet, the H436A mutant produced large, compact, and non-invasive tumors with sharp borders (p < 0.05) indicating that cell migration requires activation of G12/13. Surprisingly, immunostaining revealed that CD97 knockdown cells displayed invasive phenotype. CONCLUSIONS: Our results demonstrate the dual role CD97 plays in GBM invasion and proliferation, alluding to the molecular mechanisms that can potentially be targeted in GBM treatment.

ANGI-07. THE DUAL ROLE CD97 PLAYS IN GLIOBLASTOMA INVASION AND PROLIFERATION

Abstract INTRODUCTION Increased levels of adhesion G Protein-Coupled Receptor(GPCR) CD97 have been detected in multiple metastatic cancers. Glioblastoma(GBM), also overexpress this receptor, and its levels positively correlate with more aggressive GBM invasion. Here, using primary human GBM cells we investigated the effects of CD97 knockdown and overexpression in-vitro and in-vivo. METHODS CD97 consists of two distinct domains: the large extracellular fragment interacting with ECM and other cell surface receptors and the GPCR core that activates heterotrimeric G Proteins G12/13. To investigate the mechanism of action of CD97, we generated a CD97 knockdown (shCD97) and overexpression (CD97-WT) constructs. Additionally, we generated two functional mutants: a constitutively active mutant lacking the N-Terminus (dNTF) and dominant-negative mutant (H436A) that cannot activate G-Proteins downstream. Glioma Stem Cells(GSC) were transduced by control and CD97 lentiviral constructs and implanted into mouse brains. Once tumors formed the brains were harvested, sliced, and immunostained to evaluate invasion and proliferation. Comparing mutants to control, dunnett’s multiple comparisons test was used for statistical analysis. RESULTS Similar to CD97-WT, we found that both dNTF and H436A, increase tumor volume(p< 0.05). In contrast, the shCD97 mutant decreased tumor size(p< 0.05). Interestingly, only dNTF significantly increased tumor cell proliferation(p< 0.005), yet CD97-WT and H436A affected proliferation of non-tumor cells in the tumor bulk, indicating that this process requires the N-Terminus Fragment. In addition, over-expression of CD97-WT dramatically increases tumor invasion along myelinated fibers of corpus collosum, and tumor spread in the brain tissue(p< 0.05). Yet, the H436A mutant produced large, compact, and non-invasive tumors with sharp borders(p< 0.05) indicating that cell migration requires activation of G12/13. Surprisingly, immunostaining revealed that CD97 knockdown cells displayed invasive phenotype. CONCLUSIONS Our results demonstrate the dual role CD97 plays in GBM invasion and proliferation, alluding to the molecular mechanisms that can potentially be targeted in GBM treatment.

Use of multikinase inhibitors/lenvatinib in patients with synchronous/metachronous cancers coinciding with radioactive-resistant differentiated thyroid cancer.

This review focuses on patients with differentiated thyroid carcinoma (DTC) associated with multiple primary malignant neoplasm (MPMN) treated by multikinase inhibitors (MKIs) as systemic treatment for advanced disease. Despite the increasing frequency of MPMNs (many at an advanced stage) and the usefulness of MKIs for multiple metastatic cancers, published data on the management of MPMN and MKI therapies in this scenario are scarce. There are infrequent descriptions of patients with advanced MPMN treated with MKIs, but only a few have described advanced DTC. The management of MPMNs, including DTC and its particular circumstances, is reviewed, focusing on the evidence for MKI therapies. Some considerations for MPMN patients with advanced DTC are discussed, with the intention of helping physicians make decisions in these challenging situations and improving treatment and patient outcomes.

92P First-results of the CLIMB360 study, a prospective molecular screening program across multiple cancer types based on circulating tumor DNA (ctDNA)

Next generation sequencing in tissue is limited by sample availability and turnaround time. Here, we present the first results of the CLIMB360 study, where we performed prospective and real-time sequencing of ctDNA across multiple metastatic cancer types.

Abstract 3195: Hijacked senescence secretomes as 'immune primers' of antiangiogenic TKI efficacy

Abstract VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) and immune checkpoint inhibitors (ICIs) are approved together as a treatment regimen for multiple metastatic cancers, yet the mechanistic basis for this combinatory benefit remains unclear. Previously we have shown that resistance to VEGFR TKI treatment can transiently hijack the secretory machinery typically associated with senescence - the process of cellular aging. Here we report that these senescence-associated secretory programs can also drive immune cell activation, potentially ‘priming' the tumor for PD-1 pathway inhibition. Using a novel live-cell sorting method based on C12FDG - a substrate for senescence-associated beta-galactosidase activity - we isolated senescence-marker (SM) expressing VEGFR TKI-treated cells for transcriptomic analysis. SM+ cell populations were enriched for senescence, immune, and interferon secretory processes, with a unique gene signature validated using published preclinical and clinical datasets. Notably, SM+ cells were found to be more sensitive to CD8 T-cell mediated tumor inhibition in vivo and ex vivo and be sensitive to PD-L1 blockade and inhibitors of mTOR, a key secretory regulator. Together, these results suggest VEGFR TKI controlled secretory programs contributing to resistance can simultaneously prime the tumor microenvironment for immune cell activation, providing an explanation for improved effects of antiangiogenic and immunotherapy combinations in patients. Citation Format: Melissa Dolan, Yuhao Shi, James W. Hill, Michalis Mastri, Cristina Vaghi, Joseph Barbi, Sebastien Benzekry, John M. Ebos. Hijacked senescence secretomes as 'immune primers' of antiangiogenic TKI efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3195.

A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

As a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types.

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2 Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.

Clinicopathological and mutational differences between tumors with multiple metastases and single lung metastasis in colorectal cancer.

Cancer metastasis, particularly multiple metastatic cancer, is a significant event that affects patient prognosis. However, single metastasis can be treated by partial resection, although the clinicopathological and molecular profile of single lung metastasis has not been thoroughly elucidated. The present study examined tumor heterogeneity by comparing the mutation status between primary colorectal cancer (CRC) and corresponding metastatic lesions to identify prognostic factors associated with single lung metastasis and multiple metastases. The present study enrolled 31 cases of CRC; 20 cases with multiple metastases and 11 cases with single lung metastasis. Clinicopathologically, all cases with multiple metastases were tubular adenocarcinoma, and 3/11 cases with single metastasis were mucinous adenocarcinoma originating from the left side, the remaining 8 cases were tubular adenocarcinoma from the left side. CRC cases with multiple metastases exhibited more frequent vascular invasion, but not lymphatic invasion, than those with single lung metastasis. Furthermore, CRC with multiple metastases was associated with strong tumor budding (P=0.04). Patients with CRC with multiple metastases had lower recurrence-free survival rates compared with those with single lung metastasis (P=0.02). However, there was no significant difference between these two groups in terms of overall survival rates. A next-generation sequencing cancer hotspot panel was used to analyze a heterochronous multiple metastases case, including brain metastasis. Sanger sequencing, immunohistochemistry and microsatellite instability were examined for all 31 cases to reveal the molecular features. KRAS and TP53 mutation signatures were largely preserved throughout the metastatic events. TP53/APC mutations and overexpression of p53 appeared to be associated with the presence of lymphovascular invasion and strong tumor budding, respectively, although these differences were not statistically significant. Early relapses in patients with CRC could be a sign for eventual multiple metastases, although these may not affect the overall survival of patients with CRC. Considerable mutational changes were seemingly rare during metastatic events in patients with CRC.

Abstract B37: Development of a monoclonal antibody targeting xCT/SLC7A11 expressed in metastatic cancer cells

Abstract The cystine-glutamate antiporter xCT (SLC7A11), the light chain of the antiporter system Xc–, regulates cysteine intake and stimulates the conversion of cysteine and subsequent glutathione (GSH) synthesis, which normally protects cells from oxidative and chemical insults. xCT expression is reported to be low in normal cells but elevated in numerous cancer types, including but not limited to colorectal, breast, pancreatic, and non-small cell lung cancer. Cancer cells have adopted xCT as a means of protection from chemotherapeutic agents and to meet their increased biosynthetic and bioenergetic needs. Additionally, high levels of xCT expression have been reported to correlate with poor patient survival. Thus, our published work and the work of others have established xCT as a novel target for the treatment of metastatic cancer. We have utilized our virus-like particle (VLP) technology and knowledge of xCT to create novel therapeutic monoclonal antibodies that will bind and inhibit the function of xCT expressed on metastatic cancer cells. We bioengineered the presentation of the extracellular domain three (ECD3) of the xCT protein on the surface of our VLP platform and immunized mice to identify biologically active anti-xCT antibodies. We identified 15 subclones that were then selected based upon affinity and avidity to the VLP presenting the ECD3 peptide, the ECD3 peptide itself, and the whole xCT protein, via ELISA. Supernatants were also analyzed using immunofluorescence, to determine the ability to bind xCT expressed on HT-29 cells (human colorectal cancer cell line), MDA-BM-231 cells (human breast cancer cell line), and 4T1 spheroids (mouse breast cancer cell line). One potential candidate, mAb M5, demonstrated specific and high-affinity binding to xCT-expressing cancer cells. mAb M5 was further evaluated in an NSG mouse transplantable model (MDA-MB-231 cells), where primary tumor formation and lung metastases formation were measured. NSG mice were injected subQ with MDA-MB-231 cells and subsequently treated with the mAb M5. We observed that intraperitoneal injections of mAb M5 were able to reduce primary tumor formation and the number of lung metastases when compared to control mice. We also demonstrated in vitro that mAb M5 was able to significantly inhibit spheroid adhesion/spreading. Additionally, mAb M5 was shown in vitro to significantly reduce the uptake of FITC-cystine, which is indicative of xCT inhibition. Therefore, mAb M5 represents a potential therapeutic candidate for multiple metastatic cancer types by inhibiting the function of xCT. Citation Format: Ahmad Salameh, Jerri Caldeira, Valeria Rolih, Elisabetta Bolli, Laura Conti, Michael Perrine. Development of a monoclonal antibody targeting xCT/SLC7A11 expressed in metastatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B37.

Abstract B56: Endogenous retrovirus transcript levels are associated with immunogenic signatures in multiple metastatic cancer types

Abstract Variability in the immunogenic landscape of metastatic cancer lesions has revealed insight into detection of potential immunotherapy-responsive patients, though underlying mechanisms driving such variation are not fully understood. Endogenous retrovirus (ERV)-containing transcripts have recently emerged as a potential source of tumor-associated antigen that are orthogonal to somatic mutation-derived neoantigens. To characterize the intersection between ERV levels and predicted immunogenicity in metastatic cancer, we comprehensively profiled the transcript abundance of 702,533 ERV loci in 199 metastatic tumors from breast, colorectal, and pancreatic cancer patients. In all three cancer types, overall ERV transcript load was associated with upregulation of genes involved in innate antiviral response pathways as well as genes involved in both adaptive and innate immune signaling. In colorectal and pancreatic tumors, samples with concomitant increases in ERV load and antiviral response gene expression, termed viral mimicry tumors, showed high expression of the DNA demethylation gene TET2, a gene previously described to promote transcription of ERV-containing transcripts. Collectively, these data are compatible with the notion that an increased level of ERV-containing transcripts may account for increased immunogenicity in a subset of metastatic tumors and support the relationship between DNA demethylation and ERV load in colorectal and pancreatic tumors. Citation Format: James T. Topham, Emma Titmuss, Erin Pleasance, Laura M. Williamson, Joanna M. Karasinska, Luka Culibrk, Michael K.C. Lee, Steve E. Kalloger, Shehara Mendis, Richard A. Moore, Andrew J. Mungall, Janessa Laskin, Jonathan M. Loree, Dixie L. Mager, Marco A. Marra, Steven J.M. Jones, David F. Schaeffer, Daniel J. Renouf. Endogenous retrovirus transcript levels are associated with immunogenic signatures in multiple metastatic cancer types [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B56.

Abstract 3465: Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand

Abstract Inhibition of EGFR signaling by small molecule kinase inhibitors and monocloncal antibodies has proven effective in the treatment of multiple metastatic cancers. In contrast, metastatic breast cancer (BC) derived from EGFR-driven mammary tumors is inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here we show that in contrast to primary tumors, ligand-mediated activation of EGFR is dominated by signaling transducer and activator of transcriptional 1 (STAT1) signaling in metastatic BC. This change in downstream signaling leads to apoptosis and growth inhibition in response to EGF in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal EGFR signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death without affecting EGFR:MAPK signaling. Pharmacologic blockade of MAPK signaling through the use of the MEK1/2 inhibitor trametinib led to a dramatic increase in EGF-mediated STAT1 phosphorylation and enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, use of a trametinib:EGF combination also facilitated the apoptotic switch in EGFR function in primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental switch in EGFR in metastatic BC. Furthermore, they demonstrate that pharmacological biasing EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway. Citation Format: Remah Ali, Wells Brown, Jo Davisson, Michael Wendt. Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3465.

Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity.

MIM (Missing-in-Metastasis), also known as MTSS1 (metastasis suppressor 1), is a scaffold protein that is down-regulated in multiple metastatic cancer cell lines compared with non-metastatic counterparts. MIM regulates cytoskeletal dynamics and actin polymerization, and has been implicated in the control of cell motility and invasion. MIM has also been shown to bind to a receptor PTP (protein tyrosine phosphatase), PTPδ, an interaction that may provide a link between tyrosine-phosphorylation-dependent signalling and metastasis. We used shRNA-mediated gene silencing to investigate the consequences of loss of MIM on the migration and invasion of the MCF10A mammary epithelial cell model of breast cancer. We observed that suppression of MIM by RNAi enhanced migration and invasion of MCF10A cells, effects that were associated with increased levels of PTPδ. Furthermore, analysis of human clinical data indicated that PTPδ was elevated in breast cancer samples when compared with normal tissue. We demonstrated that the SRC protein tyrosine kinase is a direct substrate of PTPδ and, upon suppression of MIM, we observed changes in the phosphorylation status of SRC; in particular, the inhibitory site (Tyr527) was hypophosphorylated, whereas the activating autophosphorylation site (Tyr416) was hyperphosphorylated. Thus the absence of MIM led to PTPδ-mediated activation of SRC. Finally, the SRC inhibitor SU6656 counteracted the effects of MIM suppression on cell motility and invasion. The present study illustrates that both SRC and PTPδ have the potential to be therapeutic targets for metastatic tumours associated with loss of MIM.

Radius neck-to-humerus trochlea transposition elbow reconstruction after proximal ulnar metastatic tumor resection: case and literature review

Wide en bloc excision of proximal ulna sections is used to treat traumatic and pathological fractures of the ulna, though poor standardization of clinical treatment often results in long-term failure of such reconstructed biomechanical structures. In order to provide insight into effective ulnar reconstructive treatments, the case of an 80-year-old Chinese Han male presenting with pathological fracture caused by a proximal ulnar metastatic tumor concurrent with metastatic renal cancer complicated by occurrence in the brain and lungs is reported and contrasted with alternative treatment techniques. Wide resectioning of the proximal ulna and reconstruction with local radius neck-to-humerus trochlea transposition resulted in preservation of functionality, sensitivity, and biomechanical integrity after postsurgical immobilization, 6 weeks of passive- and active-assisted flexion, and extension with a hinged brace. The resultant Musculoskeletal Tumor Society rating score was 25 of 30 (83 %). Full sensitivity and mobility of the left hand and elbow (10° to 90° with minimally impaired supination and pronation) was restored with minimal discomfort. No evidence of local recurrence or other pathological complications were observed within a 1-year follow-up period. Efficient reconstruction of osseous and capsuloligamentous structures in the elbow is often accomplished by allografts, prosthesis, and soft tissue reconstruction, though wide variations in risk and prognosis associated with these techniques has resulted in disagreements regarding the most effective standards for clinical treatment. Current findings suggest that radius neck-to-humerus trochlea transposition offers a superior range of elbow movement and fewer complications than similar allograft and prosthetic techniques for patients with multiple metastatic cancers.