Ovarian cancer, a complex disease with multiple subtypes, is the fifth leading cause of cancer-related deaths among women in the United States and the third most commonly diagnosed gynecological cancer in the world. [1][2][3].
The disease, which originates in ovaries, the fallopian tubes or peritoneum, and presents subtly with vague or absent symptoms, is diagnosed often in late, advanced, stage when treatment options remain limited. If not detected early, the disease can metastasize to other areas of the body, including the liver, lungs, and brain. The efficacy of current treatment options, include surgery, chemotherapy, and radiation therapy, depends on several factors, including patient characteristics, the stage and the type of cancer, including high-grade serous, low-grade serous, mucinous ovarian cancer (MOC). [4]
Platinum-based drugs such as cisplatin are one of the most widely used chemotherapeutic drugs used in the treatment of ovarian cancer. Studies have shown that cisplatin combination therapy is more effective than alkylating agents alone or combination therapies without cisplatin.[5][6] However, one of the most significant challenges in the treatment of ovarian cancer is resistance to platinum-based drugs, that is being addresses through targeted therapies.[4]
CD99 in Ovarian cancer
A cell surface protein, known as CD99 (MIC2), plays an important, but complex role in ovarian cancer. It influences tumor growth, differentiation, and metastasis and, depending on the cellular context, can act as both an oncogene and an onco-suppressor.
Studies have shown that CD99 expression, which is often altered in ovarian cancer, is associated with cisplatin resistance. On the other hand, knockdown of CD99 sensitized ovarian cancer to cisplatin.[6] Furthermore, over-expression of CD99 can contribute to tumor progression and metastasis. [7] Survival analysis have further shown that overall survival (OS) and progression-free survival (PFS) of ovarian cancer patients patients with higher CD99 expression is generally shorter than those with lower CD99 expression.[7]
At NanoValent Pharmaceuticals, we have developed an investigational novel format nano-ADCs like Targeted NanoSpheres (nADC/TNS). Based our targeted drug delivery platform technology, we have developed NV103, an investigational CD99-targeting nADC/TNS with an irinotecan payload which selectively binds to ovarian cancer cells while largely bypassing normal, healthy, tissue, with the potential to significantly improve treatment efficacy.[8][9][10] In preclinical animal models, NV103 prolonged survival five-fold over free irinotecan treated animals in bi-weekly single dose level studies, without any treatment-related toxicity.[8]
Beyond Ovarian Cancer
Our investigational nADC/TNPs also cross the blood-brain barrier (BBB), and were used to treat orthotopic glioblastoma (GBM) PDX xenografts, prolonging animal survival 3-fold over control or free drug treated animals. Ewing sarcoma, osteosarcoma, triple negative breast cancer, glioblastoma, hepatoma, and adult ALL, bearing animals all showed complete tumor ablation and 100% survival when treated biweekly at 10mg/kg. pancreatic, prostate, and ovarian cancer showed 100% survival in NV103 treated mice after all control animals had died but remained tumor bearing with slow but progressive tumor growth when treated identically. Lung and colorectal cancer and melanoma bearing animals treated similarly with TNPs showed 50-80% survival at the time of control animal death. In these preclinical studies, our team of researchers did not observe any evidence of off-target toxicity.[10]
Reference
[1] Cabasag CJ, Fagan PJ, Ferlay J, Vignat J, Laversanne M, Liu L, van der Aa MA, Bray F, Soerjomataram I. Ovarian cancer today and tomorrow: A global assessment by world region and Human Development Index using GLOBOCAN 2020. Int J Cancer. 2022 Nov 1;151(9):1535-1541. doi: 10.1002/ijc.34002. Epub 2022 Mar 30. PMID: 35322413.
[2] Penny SM. Ovarian Cancer: An Overview. Radiol Technol. 2020 Jul;91(6):561-575. PMID: 32606233.
[3] Stewart C, Ralyea C, Lockwood S. Ovarian Cancer: An Integrated Review. Semin Oncol Nurs. 2019 Apr;35(2):151-156. doi: 10.1016/j.soncn.2019.02.001. Epub 2019 Mar 11. PMID: 30867104.
[4] Chandra A, Pius C, Nabeel M, Nair M, Vishwanatha JK, Ahmad S, Basha R. Ovarian cancer: Current status and strategies for improving therapeutic outcomes. Cancer Med. 2019 Nov;8(16):7018-7031. doi: 10.1002/cam4.2560. Epub 2019 Sep 27. PMID: 31560828; PMCID: PMC6853829.
[5] Williams CJ, Mead GM, Macbeth FR, Thompson J, Whitehouse JM, MacDonald H, Harvey VJ, Slevin ML, Lister TA, Shepherd JH, et al. Cisplatin combination chemotherapy versus chlorambucil in advanced ovarian carcinoma: mature results of a randomized trial. J Clin Oncol. 1985 Nov;3(11):1455-62. doi: 10.1200/JCO.1985.3.11.1455. PMID: 3903062.
[6] Omura G, Blessing JA, Ehrlich CE, Miller A, Yordan E, Creasman WT, Homesley HD. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. A Gynecologic Oncology Group Study. Cancer. 1986 May 1;57(9):1725-30. doi: 10.1002/1097-0142(19860501)57:9<1725::aid-cncr2820570903>3.0.co;2-j. PMID: 3513943.
[7] Wu J, Zhang L, Li H, Wu S, Liu Z. Nrf2 induced cisplatin resistance in ovarian cancer by promoting CD99 expression. Biochem Biophys Res Commun. 2019 Oct 22;518(4):698-705. doi: 10.1016/j.bbrc.2019.08.113. Epub 2019 Aug 28. PMID: 31472965
[8] HyungGyoo Kang, Jon Nagy, Bryon Upton, Timothy Triche. Superior efficacy of targeted nanoparticle therapy for brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl): Abstract nr 295.
[9] HyungGyoo Kang, Bryon Upton, Jon Nagy, Jann N. Sarkaria, Timothy J. Triche. Enhancing GBM therapy with tumor-targeted nanoparticles [abstract]. In: Proceedings of the American Association for Cancer research Annual Meeting 2025, April 25 – 30, Cgicago, Il.: AACR; 2025. Abstract nr LB183 / 1
[10] HyungGyoo Kang, Bryon Upton, Jon Nagy, Timothy Triche; Abstract 3206: Tumor-targeted nanoparticles for cancer therapy. Cancer Res 15 March 2024; 84 (6_Supplement): 3206.