Publications by authors named "Anders W Ohman"

7 Publications

  • Page 1 of 1

Defining fallopian tube-derived miRNA cancer signatures.

Cancer Med 2019 11 10;8(15):6709-6716. Epub 2019 Sep 10.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: MicroRNAs have recently emerged as promising circulating biomarkers in diverse cancer types, including ovarian cancer. We utilized conditional, doxycycline-induced fallopian tube (FT)-derived cancer models to identify changes in miRNA expression in tumors and plasma, and further validated the murine findings in high-grade ovarian cancer patient samples.

Methods: We analyzed 566 biologically informative miRNAs in doxycycline-induced FT and metastatic tumors as well as plasma samples derived from murine models bearing inactivation of Brca, Tp53, and Pten genes. We identified miRNAs that showed a consistent pattern of dysregulated expression and validated our results in human patient serum samples.

Results: We identified six miRNAs that were significantly dysregulated in doxycycline-induced FTs (P < .05) and 130 miRNAs differentially regulated in metastases compared to normal fallopian tissues (P < .05). Furthermore, we validated miR-21a-5p, miR-146a-5p, and miR-126a-3p as dysregulated in both murine doxycycline-induced FT and metastatic tumors, as well as in murine plasma and patient serum samples.

Conclusions: In summary, we identified changes in miRNA expression that potentially accompany tumor development in murine models driven by commonly found genetic alterations in cancer patients. Further studies are required to test both the function of these miRNAs in driving the disease and their utility as potential biomarkers for diagnosis and/or disease progression.
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http://dx.doi.org/10.1002/cam4.2416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825987PMC
November 2019

Nanoformulation of Talazoparib Delays Tumor Progression and Ascites Formation in a Late Stage Cancer Model.

Front Oncol 2019 10;9:353. Epub 2019 May 10.

Department of Bioengineering, Northeastern University, Boston, MA, United States.

Talazoparib, a potent PARP inhibitor, induces synthetic lethality in -deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARP inhbitors. We sought to formulate Talazoparib in a nanoparticle delivery system, which allows the drug to be administered intraperitoneally. This was done to specifically target peritoneal dissemination of late stage metastatic ovarian cancer and increase talazoparib's therapeutic efficacy while minimizing toxic side effects. NanoTalazoparib was developed and characterized with regard to its size, loading, and surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine and human cell lines and the dose response was compared to Olaparib's, the currently used PARP inhibitor. Therapeutic efficacy was tested in a peritoneal cancer model that mimics late stage disseminated disease. NanoTalazoparib has a diameter of about 70 nm with a neutral surface charge and ~75% encapsulation efficiency, which slowly releases the drug over several hours. Dose response analysis indicated that the murine cell lines with conditional , and deletions had the lowest IC50s. NanoTalazoparib administered on a schedule of three doses weekly slowed disease progression and resulted in significantly less mice with ascites at the end point compared to controls. These results indicate that the slow release nanoformulation, NanoTalazoparib, effectively delivers PARP inhibitor therapy to the peritoneal cavity for disseminated cancer treatment. The ability to decrease ascites formation with the introduction of intraperitoneal NanoTalazoparib suggests this treatment may be an effective way to treat ovarian cancer-associated ascites and slow disease progression.
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http://dx.doi.org/10.3389/fonc.2019.00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524318PMC
May 2019

Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment.

Int J Nanomedicine 2018 29;13:8063-8074. Epub 2018 Nov 29.

Department of Bioengineering, Northeastern University, Boston, MA, USA,

Background: PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy.

Methods: The tumor cell line 404, which was derived from a , , genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration.

Results: Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected.

Conclusion: NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.
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http://dx.doi.org/10.2147/IJN.S186881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278886PMC
January 2019

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.

Clin Cancer Res 2018 03 20;24(6):1389-1401. Epub 2017 Dec 20.

Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy and , decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951622PMC
March 2018

The promise and challenge of ovarian cancer models.

Transl Cancer Res 2015 Feb;4(1):14-28

Department of Pathology, Division of Women's and Perinatal Pathology, Eugene Braunwald Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

The complexity and heterogeneity of ovarian cancer cases are difficult to reproduce in studies, which cannot adequately elucidate the molecular events involved in tumor initiation and disease metastasis. It has now become clear that, although the multiple histological subtypes of ovarian cancer are being treated with similar surgical and therapeutic approaches, they are in fact characterized by distinct phenotypes, cell of origin, and underlying key genetic and genomic alterations. Consequently, the development of more personalized treatment methodologies, which are aimed at improving patient care and prognosis, will greatly benefit from a better understanding of the key differences between various subtypes. To accomplish this, animal models of all histotypes need to be generated in order to provide accurate platforms for research and the testing of targeted treatments and immune therapies. Both genetically engineered mouse models (GEMMs) and xenograft models have the ability to further our understanding of key mechanisms facilitating tumorigenesis, and at the same time offer insight into enhanced imaging and treatment modalities. While genetic models may be better suited to examine oncogenic functions and interactions during tumorigenesis, patient-derived xenografts (PDXs) are likely a superior model to assess drug efficacy, especially in concurrent clinical trials, due to their similarity to the tumors from which they are derived. Genetic and avatar models possess great clinical utility and have both benefits and limitations. Additionally, the laying hen model, which spontaneously develops ovarian tumors, has inherent advantages for the study of epithelial ovarian cancer (EOC) and recent work champions this model especially when assessing chemoprevention strategies. While high-grade ovarian serous tumors are the most prevalent form of EOC, rarer ovarian cancer variants, such as small cell ovarian carcinoma of the hypercalcemic type and transitional cell carcinoma, or non-epithelial tumors, including germ cell tumors, will also benefit from the generation of improved models to advance our understanding of tumorigenic mechanisms and the development of selective therapeutic options.
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http://dx.doi.org/10.3978/j.issn.2218-676X.2015.01.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477961PMC
February 2015

Advances in tumor screening, imaging, and avatar technologies for high-grade serous ovarian cancer.

Front Oncol 2014 18;4:322. Epub 2014 Nov 18.

Division of Women's and Perinatal Pathology, Department of Pathology, Eugene Braunwald Research Center, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA.

The majority of high-grade serous ovarian carcinoma cases are detected in advanced stages when treatment options are limited. Surgery is less effective at eradicating the disease when it is widespread, resulting in high rates of disease relapse and chemoresistance. Current screening techniques are ineffective for early tumor detection and consequently, BRCA mutations carriers, with an increased risk for developing high-grade serous ovarian cancer, elect to undergo risk-reducing surgery. While prophylactic surgery is associated with a significant reduction in the risk of cancer development, it also results in surgical menopause and significant adverse side effects. The development of efficient early-stage screening protocols and imaging technologies is critical to improving the outcome and quality of life for current patients and women at increased risk. In addition, more accurate animal models are necessary in order to provide relevant in vivo testing systems and advance our understanding of the disease origin and progression. Moreover, both genetically engineered and tumor xenograft animal models enable the preclinical testing of novel imaging techniques and molecularly targeted therapies as they become available. Recent advances in xenograft technologies have made possible the creation of avatar mice, personalized tumorgrafts, which can be used as therapy testing surrogates for individual patients prior to or during treatment. High-grade serous ovarian cancer may be an ideal candidate for use with avatar models based on key characteristics of the tumorgraft platform. This review explores multiple strategies, including novel imaging and screening technologies in both patients and animal models, aimed at detecting cancer in the early-stages and improving the disease prognosis.
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http://dx.doi.org/10.3389/fonc.2014.00322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235464PMC
December 2014

Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models.

Cancer Cell 2013 Dec;24(6):751-65

Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations.
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http://dx.doi.org/10.1016/j.ccr.2013.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917315PMC
December 2013
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