14%.
That is the grim survival rate of patients with metastasized leiomyosarcoma (LMS), a smooth muscle cancer that grows in the soft tissue inside muscles. LMS can be equally as aggressive as deadly.
This devastating statistic indicates the crucial need for new effective therapies and a deeper understanding of how this cancerous tumor develops. Cancer occurs when an abnormal group of cells rapidly divide and often destroys healthy tissue in the process. While there is a lack of attention to this form of cancer, it is still important for LMS patients and their loved ones to feel supported and informed. LMS usually grows in the uterus or the digestive system, but can also metastasize to different parts of the body.
LMS is characterized by a wide range of clinical responses and survival outcomes in patients. This isn’t ideal and can be tricky when discussing the options and life expectancy of a person’s life. Some tumors might shrink with treatment, while others resist entirely, making it difficult to find a one-size-fits-all solution (Lee et al., 2021).
Tumor removal by surgery is considered the go-to treatment for LMS. However, when surgery fails or poses a substantial threat to the patient’s health, chemotherapy, and other drug therapies are subsequently employed. Unfortunately, the drug resistance cancer biology in LMS remains poorly understood. However, what we do know is that the major challenge facing the use of systemic chemotherapies is the accumulation of toxicity. Since these chemotherapy drugs are designed to kill cancer cells, sometimes normal cells will also be affected by the drug–if too many healthy cells die, the pain can become unbearable. This can lead to treatment discontinuation, which may also cause development of multidrug resistance
Currently, the standard first-line therapy after surgery for advanced LMS typically involves certain chemotherapeutic drugs. However, these treatments offer limited success, with a median progression-free survival of around 5 months and an overall survival of 14-16 months (Lacuna et al., 2023). Consequently, there is a significant need for more effective therapeutic options.
One of the newest treatments for LMS employs/takes advantage of DNA damage repair pathways, such as by targeting defects in DNA repair mechanisms. If DNA is damaged, then there are steps to repair the DNA. However, tumor cells want to grow, and by stopping the DNA damage repair pathway, these tumor cells can stop multiplying. This has shown promise. Poly (ADP-ribose) polymerase (PARP) is an enzyme that plays a crucial role in DNA repair by detecting and then signaling DNA damage, and the inhibition of PARP can lead to cell death, particularly in cancer cells deficient in other DNA repair pathways. So, by inhibiting the DNA repair system, tumor cells can also be killed. Noticeably, these PARP inhibitors have demonstrated advances in patient outcomes. These positive outcomes are most beneficial when treatment is combined with other chemotherapy drugs (Lacuna et al., 2023).
Several PARP inhibitors have made waves in treating breast, ovarian, prostate, and pancreatic cancers (Geenen et al., 2018, Lord and Ashworth, 2017). PARP inhibitors have exhibited activity in cancers that show a deficiency in DNA repair genes. Additionally, temozolomide, a chemotherapeutic drug, was also shown to work well with PARP inhibitor treatment when used in combination with other cancer treatment, chemotherapy medicine, or cancer therapy drugs (Li et al., 2020).
Several clinical trials are investigating PARP inhibitor therapies in soft-tissue cancer patients. Early data from these studies have shown promising initial results in the context of advanced disease, which follows the failure of first-line chemotherapy, particularly in uterine LMS (Asano et al., 2022).
Leiomyosarcoma remains a challenging and deadly cancer that has continued to kill many individuals, but recent advances in targeted therapies offer a ray of hope for improved patient outcomes. The integration of molecular data into clinical practice, along with new therapeutic strategies, will be essential in helping facilitate the treatment of this aggressive disease in the future.
References
Asano H., et al. Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review. Cancers. 2022; 14(5):1180. https://doi.org/10.3390/cancers14051180
Geenen, et al. PARP Inhibitors in the Treatment of Triple-Negative Breast Cancer. Clin Pharmacokinet 57, 427–437 (2018). https://doi.org/10.1007/s40262-017-0587-4
Lacuna, Kristine, et al. “Therapeutic advances in leiomyosarcoma.” Frontiers in oncology vol. 13 1149106. 8 Mar. 2023, doi:10.3389/fonc.2023.1149106
Lee, A.T.J., et al. The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma. Sci Rep 9, 14602 (2019). https://doi.org/10.1038/s41598-019-50888-5
Li, Hongyi, et al. “Molecular signatures of BRCAness analysis identifies PARP inhibitor Niraparib as a novel targeted therapeutic strategy for soft tissue Sarcomas.” Theranostics vol. 10,21 9477-9494. 25 Jul. 2020, doi:10.7150/thno.45763