Director Vincent Center for Reproductive Biology Obstetrics & Gynecology, Massachusetts General Hospital

Associate Professor of Obstetrics, Gynecology and Reproductive Biology Obstetrics Gynecology & Repro. Bio. , Harvard Medical School

Affiliate Faculty Harvard Stem Cell Institute

Chair - Committee for Fundamental Research Massachusetts General Hospital

cancer stem cells; cell signaling; drug development; endometrial cancer; glyco-profile; gynecologic tumors; immune suppression; leiomyoma; ovarian cancer; preclinical studies; primary derived xenograft mouse models; tumor-associated carbohydrate antigens; uterine cancer; xenograft tumors

Molecular interrogation of gynecologic tumors.

My group molecularly interrogates gynecologic tumors to identify genes and proteins and their corresponding signaling pathways that contribute to malignant transformation, the pathology of the disease, recurrence and/or resistance to therapy. Once key factors or pathways are identified, we actively test novel anticancer drugs to determine their efficacy in tumor explant models. To accomplish this we maintain a GYN-focused tissue repository. The repository infrastructure is extensive and is designed to collect malignant and benign tissues along with clinically annotated information.

To complement the banking efforts my group has developed a Bio-Banking infrastructure. To this end, we utilize a well-established in vivo experimental system in which primary tumors collected from ovarian and endometrial cancer patients at the time of initial surgery are grown in NOD/SCID mice. These explanted tumors and the primary tumors are genotyped and undergo cryopreservation using state of the art techniques. Once thawed, the tumors can be propagated in vivo through serial transplantation over several passages while retaining their original genotype and histophenotype. This allows for the generation of large cohorts of matched xenograft tumors ready for use in multi-armed therapeutic experiments. Our work to date provides evidence to suggest the clinical course of the primary tumor mimics the behavior and responses we have seen in our explants further supporting the potential clinical utility of our primary xenograft model. We can use our models to assess the efficacy of dual or sequential therapy. Specifically, we assess whether novel anti-cancer agents work better as a single agent or in conjunction with the standard of care or another anti-cancer agent.

As a result of our multiple interactions with pharmaceutical companies, we have become more proactive in formulating stronger collaborations with the intent to develop novel inhibitors of oncogenic pathways, identify susceptible immune checkpoints, test new immune treatment strategies, and generate specific antibody-drug conjugates for the treatment of women diagnosed with endometrial or ovarian cancer.

---

An investigation into the functional significance of the functional contribution of gynecologic cancer stem cells.

My group has extensively studied and continues to conduct research focused on the functional contribution of subpopulations of gynecologic cancer cells that have stem-like properties. These CSCs contribute to the pathology and high recurrence rate. Our research has provided the rationale for identifying the CSCs, developing or testing novel therapies targeting these highly resistant cells. We are now focused on delineating the mechanisms which influence their bi-directional plasticity.   

---

An investigation into the functional significance of aberrant forms of glycosylation in gynecologic cancers.

Tumor-associated carbohydrate antigens (TACAs) are promising therapeutic targets. An increased presence of Sialyl-Thomsen-nouveau antigen (STn), a TACA, correlates with worsened outcome and chemoresistance in ovarian cancer (OvCa). Our recent studies suggest that many of the previously published reports that supported this conclusion utilized STn antibodies that may not be as specific as originally proposed. We are working with a panel of murine and humanized antibodies that bind with high specificity to all glycoforms of STn.  Our preliminary data utilizing these novel highly specific STn antibodies suggests that STn is present in a significant subset of OvCa cells and tumors. From a therapeutic standpoint, we are testing STn-antibody drug conjugates (ADC) in in vitro and in vivo models. Moreover, we are in the process of developing a companion diagnostic to assess which patient population may best benefit from an STn directed therapy. 

Independently, we are investigating how aberrant glycosylation promotes an immunosuppressive tumor microenvironment.

---

Define mechanisms that contribute to the genesis, progression or pathology of benign gynecologic diseases.

In addition to in-depth studies on gynecologic malignancies, we also focus on benign diseases that impact reproductive-aged women. Specifically, we have and continue to be focused on endometriosis and leiomyoma. These non-malignant diseases can have a devastating negative impact on women's health and quality of life.

Despite the prevalence of the disease, very little progress has been made in long-term solutions with the exception of surgical removal of the uterus.

We have used mouse models as well as primary human tissues to assess the mechanisms by which specific cell-signaling factors positively or negatively impact the development, progression and/or pathological properties associated with these diseases.