Publications

Director, Stanford Gynecologic Oncology Fellowship (2016 - Present) Director, Stanford Clinical Research Group for Gynecologic Cancer Trials (2014 - Present) Director, Stanford Gynecologic Oncology Clinical Care Program (2013 - Present) Director, Mary Lake Polan Gynecologic Oncology Research Laboratory (2013 - Present) Director, Stanford Obstetrics and Gynecology, Division of Gynecologic Oncology (2013 - Present)

Publications

  • Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1. Communications biology Krishnan, V., Tallapragada, S., Schaar, B., Kamat, K., Chanana, A. M., Zhang, Y., Patel, S., Parkash, V., Rinker-Schaeffer, C., Folkins, A. K., Rankin, E. B., Dorigo, O. 2020; 3 (1): 524

    Abstract

    The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of chemokine ligandCCL6 in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.

    View details for DOI 10.1038/s42003-020-01246-z

    View details for PubMedID 32963283

  • Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet (London, England) Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A. A., O'Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., Churchman, M., Ewing, A., Hollis, R. L., Herrington, C. S., Huang, H. Q., Wenzel, L., Gourley, C. 2022; 399 (10324): 541-553

    Abstract

    BACKGROUND: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma.METHODS: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40-50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting.FINDINGS: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9-15·0) compared with 7·2 months (5·6-9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36-0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths.INTERPRETATION: Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.FUNDING: NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.

    View details for DOI 10.1016/S0140-6736(21)02175-9

    View details for PubMedID 35123694

  • Cell-based immunotherapies in gynecologic cancers. Current opinion in obstetrics & gynecology Lang, S. M., Dorigo, O. 1800; 34 (1): 10-14

    Abstract

    PURPOSE OF REVIEW: This review provides an update on recent developments in cell-based immunotherapy in gynecologic cancers.RECENT FINDINGS: Chimeric antigen receptor (CAR) technology has made significant progress allowing now for not only expressing CARs on T-cells, but also on other immune effector cells, such as natural killer cells and macrophages. Cell-based vaccines have started to show promising results in clinical trials.SUMMARY: Cell-based immunotherapies in gynecologic cancers continue to evolve with promising clinical efficacy in select patients.

    View details for DOI 10.1097/GCO.0000000000000760

    View details for PubMedID 34967809

  • Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial LANCET Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A., O'Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., Churchman, M., Ewing, A., Hollis, R. L., Herrington, C., Huang, H. Q., Wenzel, L., Gourley, C. 2022; 399 (10324): 541-553
  • Evidence-Based Clinical Practice Guidelines for Extramammary Paget Disease. JAMA oncology Kibbi, N., Owen, J. L., Worley, B., Wang, J. X., Harikumar, V., Downing, M. B., Aasi, S. Z., Aung, P. P., Barker, C. A., Bolotin, D., Bordeaux, J. S., Cartee, T. V., Chandra, S., Cho, N. L., Choi, J. N., Chung, K. Y., Cliby, W. A., Dorigo, O., Eisen, D. B., Fujisawa, Y., Golda, N., Halfdanarson, T. R., Iavazzo, C., Jiang, S. I., Kanitakis, J., Khan, A., Kim, J. Y., Kuzel, T. M., Lawrence, N., Leitao, M. M., MacLean, A. B., Maher, I. A., Mittal, B. B., Nehal, K. S., Ozog, D. M., Pettaway, C. A., Ross, J. S., Rossi, A. M., Servaes, S., Solomon, M. J., Thomas, V. D., Tolia, M., Voelzke, B. B., Waldman, A., Wong, M. K., Zhou, Y., Arai, N., Brackett, A., Ibrahim, S. A., Kang, B. Y., Poon, E., Alam, M. 2022

    Abstract

    Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms.To develop recommendations for the care of adults with EMPD.A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD.The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

    View details for DOI 10.1001/jamaoncol.2021.7148

    View details for PubMedID 35050310

  • Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer. Molecular cancer therapeutics Eggold, J. T., Chow, S., Melemenidis, S., Wang, J., Natarajan, S., Loo, P. E., Manjappa, R., Viswanathan, V., Kidd, E. A., Engleman, E., Dorigo, O., Loo, B. W., Rankin, E. B. 2021

    Abstract

    Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise, however current clinical trials are limited by modest response rates. Radiation therapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. While ultra-high dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, the immunomodulatory properties of FLASH irradiation remain unknown. Here we demonstrate that single high dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared to conventional irradiation, FLASH irradiation increased intratumoral T cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T cell infiltration and enhance the efficacy of alphaPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

    View details for DOI 10.1158/1535-7163.MCT-21-0358

    View details for PubMedID 34866044

  • Phase II Trial Evaluating Efficacy of a Fitbit Program for Improving the Health of Endometrial Cancer Survivors Rahimy, E., Usoz, M., von Eyben, R., Fujimoto, D., Watanabe, D., Karam, A., Jairam-Thodla, A., Mills, M., Dorigo, O., Diver, E., Teng, N., English, D., Kidd, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S13
  • Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling. The Journal of clinical investigation Qian, J., LeSavage, B. L., Hubka, K. M., Ma, C., Natarajan, S., Eggold, J. T., Xiao, Y., Fuh, K. C., Krishnan, V., Enejder, A., Heilshorn, S. C., Dorigo, O., Rankin, E. B. 2021; 131 (16)

    Abstract

    Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-beta signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.

    View details for DOI 10.1172/JCI146186

    View details for PubMedID 34396988

  • Classification of molecular subtypes of high-grade serous ovarian cancer by MALDI-Imaging. Kassuhn, W., Klein, O., Darb-Esfahani, S., Lammert, H., Handzik, S., Taube, E. T., Schmitt, W. D., Dorigo, O., Horst, D., Keunecke, C., Dreher, F., George, J., Bowtell, D., Hummel, M., Sehouli, J., Bluethgen, N., Kulbe, H., Braicu, E. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2). Nature communications Swisher, E. M., Kwan, T. T., Oza, A. M., Tinker, A. V., Ray-Coquard, I., Oaknin, A., Coleman, R. L., Aghajanian, C., Konecny, G. E., O'Malley, D. M., Leary, A., Provencher, D., Welch, S., Chen, L., Wahner Hendrickson, A. E., Ma, L., Ghatage, P., Kristeleit, R. S., Dorigo, O., Musafer, A., Kaufmann, S. H., Elvin, J. A., Lin, D. I., Chambers, S. K., Dominy, E., Vo, L., Goble, S., Maloney, L., Giordano, H., Harding, T., Dobrovic, A., Scott, C. L., Lin, K. K., McNeish, I. A. 2021; 12 (1): 2487

    Abstract

    ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.

    View details for DOI 10.1038/s41467-021-22582-6

    View details for PubMedID 33941784