Leiomyosarcoma (LMS) is a leading subtype of soft tissue sarcomas, characterized as a malignant tumor of smooth muscle tissue. Protheragen provides a comprehensive suite of services dedicated to advancing LMS diagnostics and therapeutics. We offer end-to-end solutions, from target identification and validation to lead compound optimization and preclinical efficacy testing.
Overview of Leiomyosarcoma (LMS)
Leiomyosarcoma (LMS) is an uncommon and deeply aggressive type of soft tissue sarcoma (STS) that arises from smooth muscle cells. It shows considerable disease heterogeneity, with potential uterine, abdominal, retroperitoneal, or even vascular origins. In adults, it is one of the most common subtypes, constituting 10-20% of new soft tissue sarcoma (STS) diagnoses. Although LMS is primarily surgically treated, it tends to recur locally and metastasize, most frequently to the lungs. LMS is more common with advancing age, particularly around 70, and is seen more often in the perimenopausal phase of women.
Fig.1 Histopathologic characterization and molecular subtyping of LMS. (Devaud N.,
et al., 2022)
Pathogenesis of Leiomyosarcoma (LMS)
The development of LMS is intricate, involving a deep degree of genomic instability. LMS tumors display high levels of mutational heterogeneity, with numerous somatic mutations, extensive whole-genome duplications, widespread alterations in DNA copy-number, alongside chromothripsis. Some of the critical genomic alterations are mutational or deletions in the tumor suppressor genes, including the RB1, PTEN, and TP53. Furthermore, LMS is characterized by some defects in DNA damage repair pathways, especially in genes responsible for homologous recombination (HR). Other molecular changes include mutations within genes responsible for the maintenance of telomeres, such as ATRX. Although the LMS tumors' exact causes are not well elucidated, some genetic predispositions, such as retinoblastoma and Li-Fraumeni Syndrome, are known to increase the likelihood of developing LMS.
Diagnostics Development for Leiomyosarcoma (LMS)
- Molecular Profiling
Molecular profiling for LMS includes whole-genome sequencing alongside RNA transcriptomes and methylation profiling. Such techniques have been able to identify and classify three molecular subtypes of LMS, each having distinct clinical and anatomical correlations. For instance, subtype I has a favorable prognosis and expresses genes associated with smooth muscle differentiation, while subtype II, with a poorer prognosis, expresses fewer smooth muscle differentiation genes. Predominantly, uterine LMS, subtype III, has an intermediate outcome.
- Imaging Techniques
Imaging methods like Computed Tomography (CT) scans, Magnetic Resonance Imaging (MRI), and Positron Emission Tomography combined with Computed Tomography (PET-CT) are essential for assessing the size, local spread, and metastatic spread of LMS (Leiomyosarcoma) tumors and their metastases. MRI has particular utility in evaluating the relationship of the tumor to adjacent organs and distinguishing between an intravascular tumor and thrombus. Additionally, PET-CT has value in assessing metabolic activity and grading the tumor.
Therapeutics Development for Leiomyosarcoma (LMS)
- Targeted Therapy
Targeted therapies include PARP inhibitors (e.g., olaparib) in combination with DNA-damaging agents (e.g., temozolomide) for patients with HR-deficient tumors. Other targeted agents under investigation include ATR inhibitors and DNA-PK inhibitors. For instance, the combination of olaparib and temozolomide has demonstrated a response rate of 27% in heavily pretreated patients with uterine LMS.
- Immunotherapy
Immunotherapy approaches include immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab) and combinations with chemotherapy or targeted agents. Emerging strategies involve targeting the tumor immune microenvironment, such as CD40 agonists and CSF1 receptor inhibitors. For example, the combination of nivolumab and ipilimumab has shown a 45% overall response rate and a median PFS of 14.4 months in patients with LMS.
Table 1. Selected ongoing clinical trials in leiomyosarcoma. (Lacuna K., et al., 2023)
| NCT Identifier |
Title |
Phase |
Line of Therapy |
Eligible Subtypes |
Status |
| NCT05633381 |
Testing Olaparib and Temozolomide Versus the Usual Therapy for Uterine Leiomyosarcoma After Chemotherapy Has Stopped Working |
2/3 |
> 2 |
uLMS |
Recruiting |
| NCT05116683 |
ATX-101 in Advanced Dedifferentiated Liposarcoma and Leiomyosarcoma (ATX-101) |
2 |
> 1 |
LMS |
Recruiting |
| NCT04807816 |
Targeting ATR in Soft-tissue Sarcomas (TARSARC) |
2 |
0-4 |
LMS |
Recruiting |
| NCT03536780 |
Avetumab in Combination with Gemcitabine in Advanced Leiomyosarcoma as a Second-line Therapeutic (EAGLES) |
2 |
> 1 |
LMS |
Recruiting |
| NCT04577014 |
Retifanlimab (Anti-PD-1 Antibody) With Gemcitabine and Docetaxel in Patients with Advanced Soft Tissue Sarcoma |
1/2 |
First |
STS including LMS |
Recruiting |
| NCT03138161 |
SAINT: Trabectedin, Ipilimumab, and Nivolumab as First-Line Therapeutic for Advanced Soft Tissue Sarcoma |
1/2 |
>1 (Phase 1); First (Phase 2) |
STS including LMS |
Recruiting |
| NCT04551430 |
Cabozantinib Combined With PD-1 and CTLA-4 Inhibition in Metastatic Soft Tissue Sarcoma |
2 |
2-3 |
STS including LMS |
Recruiting |
| NCT04624178 |
A Study of Rucaparib and Nivolumab in People with Leiomyosarcoma |
2 |
2-4 |
LMS |
Not recruiting |
| NCT04242238 |
A Phase 1b Dose Escalation and Dose Expansion Study of a CSF1R Inhibitor (DCC-3014) Administered Concurrently with an Anti-PD-L1 Antibody (Avelumab) in Patients with Advanced High-grade Sarcoma |
1b |
> 1 |
STS including LMS |
Not recruiting |
| NCT03719430 |
APX005M and Doxorubicin in Advanced Sarcoma |
2 |
Any |
STS including LMS |
Recruiting |
| NCT04996004 |
A Study to Learn About the Study Medicine (Called TTI-621) Given Alone and in Combination with Doxorubicin in People with Leiomyosarcoma (TTI-621-03) |
2 |
Second |
LMS |
Recruiting |
| NCT04200443 |
Cabozantinib and Temozolomide for the Therapeutic of Unresectable or Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma |
2 |
0-5 |
STS including LMS |
Recruiting |
| NCT03016819 |
Phase III Trial of Anlotinib, Catequintin in Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma, Synovial Sarcoma (APROMISS) |
3 |
> 1 |
STS including LMS |
Not recruiting |
| NCT05269355 |
A Study of Unesbulin in Participants with Advanced Leiomyosarcoma (LMS) (SUNRISELMS) |
2/3 |
> 1 |
LMS |
Recruiting |
LMS, leiomyosarcoma; uLMS, uterine leiomyosarcoma; STS, soft tissue sarcoma.
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive services for the development of diagnostics and therapeutics for Leiomyosarcoma (LMS). Our services include molecular profiling, imaging analysis, and percutaneous biopsy to support accurate diagnosis. We also provide preclinical research services to evaluate the efficacy and safety of new drugs and therapies. Our customized services are designed to meet the specific needs of each client, ensuring that their research and development goals are achieved efficiently and effectively.
Disease Models
- PTEN Knockout Mouse Models
- p53 and BRCA1 Knockout Mouse Models
- SV40 T Antigen Transgenic Mouse Models
- Cripto-1 Transgenic Mouse Models
- LMP2 Knockout Mouse Models
Protheragen's preclinical research services for LMS include in vitro and in vivo studies to evaluate the efficacy of new drugs and combinations. Our state-of-the-art facilities and expert scientists ensure that our clients receive high-quality data and insights to support their research and development efforts. If you are interested in our services, please feel free to contact us.
References
- Devaud, Nicolas, et al. "Leiomyosarcoma: current clinical management and future horizons." Surgical Oncology Clinics 31.3 (2022): 527-546.
- Lacuna, Kristine, et al. "Therapeutic advances in leiomyosarcoma." Frontiers in Oncology 13 (2023): 1149106.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
