Featured Image: Teal ribbon awareness to support Ovarian/Cervical Cancer on human hand old aged wood background. Courtesy: © 2018. Fotolia Used with permission.

Patients diagnosed with ovarian cancer may have persistent, refractory or recurrent cancer following treatment with surgery and first-line chemotherapy. Generally, persistent cancer refers to the occurrence of residual cancer growth – cells that persist during and following initial treatment.

Called recurrent ovarian cancer, is thought to result in part from the inability to eliminate rare quiescent cancer stem cells (CSCs) that survive cytotoxic chemotherapy and drive tumor resurgence.

Although researchers have made major improvements in the treatment of ovarian cancer, in more than 70% of patients initial or first-line chemotherapy fails to produce a remission. And approximately 40-50% of the women who achieve a remission after first-line treatment experience a recurrence of cancer within 3 years.

Scientists at Siamab Therapeutics, a biopharmaceutical company developing novel glycan-targeted cancer therapeutics, have found that ST1 antibody drug conjugate (ADC) targeting the tumor-associated carbohydrate antigen (TACA) Sialyl-Tn (STn), may inhibits growth of chemoresistant ovarian tumor cells expressing STn in vitro and in vivo.

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STn is present on multiple solid tumors and is associated with a chemoresistant population in ovarian cancer. The findings show that ST1-ADC selectively inhibits tumor cell proliferation and induces tumor cell death in both in vitro and in vivo ovarian cancer models.

Image 1.0: Anti-STn ADCs impede OvCa xenograft growth in vivo and target STn+ cells. (A) Mice bearing tumors derived from OVCAR3 were treated with vehicle, unconjugated S3F, S3F-CL-MMAE, unconjugated 2G12-2B2, or 2G12-2B2-CL-MMAE. Tumors were measured twice weekly, and the percentage change in tumor volume compared to the baseline volume (100%) is shown. Error bars represent the mean ± SEM *p < 0.05. (B) Xenografts collected at the end of the in vivo treatment were examined to assess the relative frequency of STn-/CD133-, STn+/CD133-, STn-/CD133+ and STn+/CD133+ sub-populations. Courtesy: © 2018. Siamab Therapeutics. Used with permission.

ST1, Siamab’s lead program, is in late stage preclinical development for the treatment of STn-expressing solid tumors. The data, generated through a collaboration with Bo Rueda, Ph.D., Director of The Vincent Center for Reproductive Biology at Massachusetts General Hospital, have been published online in the May 2018 edition of  Oncotarget. [1]

The published study results show that STn is expressed on ovarian cancer cells and is frequently co-expressed with the established ovarian cancer stem cell (CSC) marker CD133. Importantly, STn positive and CD133 positive cells persist following cytotoxic chemotherapy. Furthermore, the results show that treatment with Siamab’s ST1 ADCs reduced the viability of STn positive ovarian cancer cell lines in vitro and reduced tumor volume in vivo in an ovarian cancer xenograft mouse model, depleting STn positive tumor cells. No significant changes in mouse weight were observed during treatment and no other toxicities were noted.

“These findings are important as they hold promise for the development of new therapeutic options to treat ovarian cancer,” said Jeff Behrens, president and chief executive officer of Siamab.

“The results show that targeting the STn antigen expressed on ovarian tumor cells and, critically, chemoresistant cells, with an anti-STn ADC can selectively inhibit tumor cell proliferation and induce tumor cell death in both in vitro and in vivo models. Furthermore, the studies suggest that either combination or sequential coupling of anti-STn therapy with conventional cytotoxic chemotherapy could target both bulk tumor and chemoresistant cells that play an important role in disease recurrence,” Behrens explained.

Ovarian cancer is the most lethal gynecologic cancer, with more than 22,400 diagnoses and over 14,000 deaths projected in 2018.1 This is due primarily to the lack of reliable early detection methods, resulting in greater than 75% of patients presenting with advanced stage disease. Unfortunately, despite aggressive surgery and adjuvant platinum-based chemotherapy with taxane, which is the standard of care2, most women with ovarian cancer develop recurrent disease that is ineffectively treated with current therapies.

“Recurrent ovarian cancer is thought to result in part from the inability to eliminate rare chemoresistant CSCs that survive cytotoxic chemotherapy and drive tumor resurgence,” Rueda said.

“The ability to identify markers of chemoresistant cells is central to developing new therapeutic strategies that target these cells and ultimately provide clinical impact by reducing disease recurrence. Data from this study suggest a potential role for highly specific, glycan-targeted therapy in ovarian cancer treatment,” Rueda added.

Siamab’s proprietary technology platform enables the development of highly specific monoclonal antibody (mAb) therapeutics, including ADCs, targeting cancer cell surface glycans called TACAs. TACAs are an emerging set of tumor-specific antigens implicated in immune suppression, chemoresistance and a CSC phenotype.

The presence of STn on tumors is generally associated with metastatic disease, poor prognosis, and reduced overall survival.


Last Editorial Review: May 2, 2018

Featured Image: Teal ribbon awareness to support Ovarian/Cervical Cancer on human hand old aged wood background. Courtesy: © 2018. Fotolia Used with permission. Image 1.0: Anti-STn ADCs impede OvCa xenograft growth in vivo and target STn+ cells. (A) Mice bearing tumors derived from OVCAR3 were treated with vehicle, unconjugated S3F, S3F-CL-MMAE, unconjugated 2G12-2B2, or 2G12-2B2-CL-MMAE. Tumors were measured twice weekly, and the percentage change in tumor volume compared to the baseline volume (100%) is shown. Error bars represent the mean ± SEM *p < 0.05. (B) Xenografts collected at the end of the in vivo treatment were examined to assess the relative frequency of STn-/CD133-, STn+/CD133-, STn-/CD133+ and STn+/CD133+ sub-populations. Courtesy: © 2018. Siamab Therapeutics. Used with permission.

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