Abstract 127P
Background
Bone-resident cancer types such as multiple myeloma, osteosarcoma and metastatic prostate cancer are frequently not amiable to surgery when occupying the bone. For small molecule therapeutics for these cancer types, specific-targeting of the cancer also allows for reduced peripheral toxicity. We know that for bone-resident cancers, their number one characteristic is the recruitment of bone-remodeling cells such as osteoclasts and osteoblasts as they breakdown existing bone and form new bone around the tumor. Another of their characteristics is the acidification of the bone-compartment that they occupy. For these cancer types, the metabolic pathway of mTORC1 is also frequently and constitutively upregulated.
Methods
Small molecule mTORC1 inhibitor, sirolimus, was chemically conjugated to alendronate, a bisphosphanate. The linkage was covalent and acid-cleavable. The molecule was tested for potency in being able to inhibit mTORC1 and being able to bind to the bone-matrix, hydroxyapatite, and being released when exposed to the low pH of a tumor microenvironment. A NOG (NOD/Shi-scid/IL-2Rγnull) mouse model of ectopic bone-resident multiple myeloma (RPMI8226) was established, and the injected molecule was tested for reaching the bone-tumor site (anti-sirolimus detection of the small molecule) and blocking its target (anti-S6 kinase staining of the mouse bone-tumor samples). Blood samples were analyzed for liver and kidney markers of toxicity and mouse weights were monitored.
Results
The conjugated and modified sirolimus was able to reach the tumor site via tail-vein injection and block the activity of its target mTORC1. There was also a sizable decrease in tumor size. In addition, there were no adverse effects in terms of weight loss. There were also no adverse changes in the liver or kidney function from a two-week monitoring of the repeatedly-injected compound.
Conclusions
The modified mTORC1 inhibitor was able to effectively target the bone-resident tumor and reach its target and block it with no overt toxicity. This inhibitor also showed utility in targeting a bone-resident cancer, releasing a specific therapeutic to the remodeled bone in the tumor periphery.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
Hallym University (S. Korea) Ewha Womans University (S. Korea).
Funding
National Research Foundation of Korea (NRF) funded by the Ministry of Science (S. Korea).
Disclosure
The author has declared no conflicts of interest.
Resources from the same session
51P - Functional characterization of the novel long intergenic non-coding RNA-RFC4, a transcript regulating chromosomal instability in prostate cancer
Presenter: Rogelio Montiel Manríquez
Session: Cocktail & Poster Display session
Resources:
Abstract
52P - The concentration of mutated copies of driver genes in plasma closely mirrors the disease course in colorectal cancer, lung cancer, and melanoma patients
Presenter: Ekaterina Kuligina
Session: Cocktail & Poster Display session
Resources:
Abstract
53P - Heterogeneous characteristics of KRAS mutation subtypes in surgically resected lung adenocarcinomas
Presenter: Kazuya Takamochi
Session: Cocktail & Poster Display session
Resources:
Abstract
54P - ATRX-deficient IDH-wildtype adult high-grade gliomas display novel, clinically relevant genetic patterns by comprehensive genomic profiling
Presenter: Gábor Bedics
Session: Cocktail & Poster Display session
Resources:
Abstract
55P - EGFR variant allele frequency (VAF) impacts on metastatic NSCLC patients outcome during first-line osimertinib
Presenter: Silvia Teresa Riva
Session: Cocktail & Poster Display session
Resources:
Abstract
57P - Clinical characteristics and outcomes in non-small cell lung cancer (NSCLC) with tumour and germline BRCA1/2 mutations
Presenter: Greydon Arthur
Session: Cocktail & Poster Display session
Resources:
Abstract
58P - Molecular investigation using microarray-based comparative genomic hybridization in patients with myelodysplastic syndrome and normal karyotype
Presenter: Mohamed abd naceur AMMAR
Session: Cocktail & Poster Display session
Resources:
Abstract
59P - Unraveling methylation signatures in RAS/BRAF wild-type colorectal cancer patients to identify predictive biomarkers for anti-epidermal growth factor receptor therapy
Presenter: Ana Regina de Abreu
Session: Cocktail & Poster Display session
Resources:
Abstract
60P - Spindle cell sarcomas with tyrosine kinase rearrangement
Presenter: Lenka Krsková
Session: Cocktail & Poster Display session
Resources:
Abstract
61P - Deconvoluting the intra-tumour heterogeneity and subclonal evolution of CDK4/6 inhibitor resistance in ER+ breast cancer
Presenter: Ioanna Mavrommatis
Session: Cocktail & Poster Display session
Resources:
Abstract