Neeraj Kohli

Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis

Computational modeling of the ErbB signaling network affirms ErbB3 as a therapeutic target. Zooming In on ErbB3 Aberrant signaling involving the ErbB family of receptors, which can signal as homo- or heterodimers to activate the phosphatidylinositol 3-kinase (PI3K) signaling pathway, has been implicated as contributing to various cancers. Using a systems approach, Schoeberl et al. implicated ErbB3—a member of the ErbB family that is catalytically inactive—as critical to signaling stimulated by ligands that bind either ErbB1 or ErbB3. Computational analysis suggested that inhibiting ligand binding to ErbB3 might represent a more successful approach to treating cancers associated with ligand-induced stimulation of ErbB-PI3K signaling mediated by combinatorial receptor activation than do current therapies that target overexpressed or mutationally activated ErbB-family receptors. Moreover, experimental analysis revealed that a monoclonal antibody developed on the basis of this strategy could stop the growth of tumors grafted into immunodeficient mice. The signaling network downstream of the ErbB family of receptors has been extensively targeted by cancer therapeutics; however, understanding the relative importance of the different components of the ErbB network is nontrivial. To explore the optimal way to therapeutically inhibit combinatorial, ligand-induced activation of the ErbB–phosphatidylinositol 3-kinase (PI3K) axis, we built a computational model of the ErbB signaling network that describes the most effective ErbB ligands, as well as known and previously unidentified ErbB inhibitors. Sensitivity analysis identified ErbB3 as the key node in response to ligands that can bind either ErbB3 or EGFR (epidermal growth factor receptor). We describe MM-121, a human monoclonal antibody that halts the growth of tumor xenografts in mice and, consistent with model-simulated inhibitor data, potently inhibits ErbB3 phosphorylation in a manner distinct from that of other ErbB-targeted therapies. MM-121, a previously unidentified anticancer therapeutic designed using a systems approach, promises to benefit patients with combinatorial, ligand-induced activation of the ErbB signaling network that are not effectively treated by current therapies targeting overexpressed or mutated oncogenes.

Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3

The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse. Mol Cancer Ther; 11(3); 582–93. ©2012 AACR.

The anatomic and functional outcomes of defect-specific rectocele repairs

OBJECTIVE This study was undertaken to evaluate the anatomic, functional, and quality-of-life effects of site-specific posterior colporrhaphy in the surgical management of rectocele. STUDY DESIGN In a retrospective observational study 125 patients were studied who had undergone site-specific posterior colporrhaphy between 1995 and 1996, either alone or in conjunction with other pelvic procedures. Physical examination was performed >/=6 months after the operation to assess the anatomic success of the repair. Standardized questionnaires were used to assess quality of life, sexual function, and bowel function. RESULTS Surgical correction was found at follow-up examination to have been achieved in 82% of eligible patients (73/89). All daily aspects of living improved significantly (P <.05), including ability to do housework (56% improvement or cure), travel (58% improvement or cure), and social activities (60% improvement or cure). Emotional well-being also significantly improved after the operation, as measured by thoughts of embarrassment (57% improvement or cure) or frustration (71% improvement or cure). Sexual function was not affected; however, reports of dyspareunia significantly (P <.04) improved or were cured after the operation in 73% of patients (19/26), worsened in 19% of patients (5/26), and arose de novo in 3 patients. Results showed no other significant differences in vaginal dryness, orgasm ability, sexual desire, sexual frequency, or sexual satisfaction. Bowel symptoms were assessed subjectively and were noted to have significantly improved (P <.008) after the operation. The following improvement or cure rates were obtained: stooling difficulties, 55%; pelvic pain or pressure, 73%; vaginal mass, 74%; and splinting, 65%. CONCLUSION This study indicates that defect-specific posterior colporrhaphy is equal to or superior to traditional posterior colporrhaphy. This type of repair provides durable anatomic support and is successful in restoring bowel function. It does not detrimentally affect sexual function, may aid in the resumption of sexual activity, and significantly improves quality of life and social aspects of daily living.

Mesh erosion after abdominal sacrocolpopexy

Objective To report our experience with erosion of perma-nent suture or mesh material after abdominal sacrocol-popexy. Methods A retrospective chart review was performed to identify patients who underwent sacrocolpopexy by the same surgeon over 8 years. Demographic data, operative notes, hospital records, and office charts were reviewed after sacrocolpopexy. Patients with erosion of either suture or mesh were treated initially with conservative therapy fol-lowed by surgical intervention as required. Results Fifty-seven patients underwent sacrocolpopexy using synthetic mesh during the study period. The mean (range) postoperative follow-up was 19.9 (1.3–50) months. Seven patients (12%) had erosions after abdominal sacrocol-popexy with two suture erosions and five mesh erosions. Patients with suture erosion were asymptomatic compared with patients with mesh erosion, who presented with vagi-nal bleeding or discharge. The mean (6 66 standard deviation) time to erosion was 14.0 6 66 7.7 (range 4–24) months. Both patients with suture erosion were treated conservatively with estrogen cream. All five patients with mesh erosion required transvaginal removal of the mesh. Conclusion Mesh erosion can follow abdominal sacrocol-popexy over a long time, and usually presents as vaginal bleeding or discharge. Although patients with suture ero-sion can be managed successfully with conservative treat-ment, patients with mesh erosion require surgical interven-tion. Transvaginal removal of the mesh with vaginal advancement appears to be an effective treatment in patients failing conservative management.

Release of tension-free vaginal tape for the treatment of Refractory postoperative voiding dysfunction

OBJECTIVE To report our experience with surgical release of tension‐free vaginal tape (TVT) for the treatment of persistent post‐TVT voiding dysfunction. METHODS A total of 1175 women underwent TVT placement for treatment of genuine stress urinary incontinence and/or intrinsic sphincter deficiency over a 2‐year period. Additional procedures and vaginal repairs were performed as indicated. Among these patients, 23 women (1.9%) had persistent voiding dysfunction (urinary retention, incomplete bladder emptying, or severe urgency or urge incontinence) refractory to conservative management. This cohort underwent a simple vaginal TVT release procedure, performed on an outpatient basis. Preoperative characteristics, intraoperative, and postoperative details were assessed by review of operative notes, medical records, and office notes. Continence status was assessed using subjective and objective information. RESULTS Mean age was 67 years (range 46–86 years), and the mean interval between TVT placement and release was 17.3 weeks (range 2–69 weeks; median 8.6 weeks). For the release procedure, there were no intraoperative complications, and all patients were discharged on the day of surgery. All cases of impaired emptying were completely resolved, and all cases of irritative symptoms were resolved (30%) or improved (70%) by 6 weeks. Fourteen (61%) patients remained continent 6 weeks after the release procedure, six (26%) were improved over baseline, and three patients (13%) had recurrence of stress incontinence. CONCLUSION Refractory voiding dysfunction after TVT is a relatively uncommon situation and can be successfully managed with a simple midline release procedure. In most cases, the release procedure does not compromise overall improvement in symptoms of stress incontinence.

The age distribution, rates, and types of surgery for pelvic organ prolapse in the USA

The objective of this study was to describe the distribution of pelvic organ prolapse (POP) surgery across age groups in the USA in 2003. Patients were grouped into four age categories: Reproductive age, perimenopausal, postmenopausal, and elderly. Data from the 2003 National Hospital Discharge Survey and National Census were used to estimate surgical rates by age group. In 2003, 199,698 women underwent a total of 311,587 surgical procedures for POP. Prolapse surgical rates (per 10,000 women) were 7, 24, 31, and 17 in reproductive age, perimenopausal, postmenopausal, and elderly age groups, respectively. Surgical complications occurred in 28.8, 19.6, 18.6, and 22.1% of women in these age groups, respectively. Mortality was uncommon. Although often considered a condition of the elderly, this study suggests that pelvic organ prolapse is a condition affecting women across the reproductive life cycle and for which women of all ages seek surgical treatment.

Dermal graft-augmented rectocele repair

We describe a new technique in the surgical treatment of rectocele using a dermal allograft to augment site-specific fascial defect repair of the rectovaginal fascia. The posterior vaginal wall is opened and discrete defects in the rectovaginal fascia are repaired in a site-specific fashion using delayed absorbable suture. A second layer of support is created using a rectangular dermal allograft placed over the site-specific repair and secured to the normal anatomic attachments of the rectovaginal fascia using permanent sutures. The vagina is then closed and routine perineorrhaphy performed as indicated. Forty-three women with advanced posterior vaginal wall prolapse underwent dermal graft augmentation of site-specific rectocele repair over a 1-year period. No major intraoperative or postoperative complications were reported. Thirty women were available for follow-up examination at an average of 12.9 months (range 8–17). The average patient age in the follow-up group was 63.6 ± 10.9 years (range 33–79) and average parity was 2.8 ± 1.5 (range 0–7). Using the Pelvic Organ Prolapse Quantification score, the average measurement of point Ap was 0.25 preoperatively and −2.4 postoperatively, whereas point Bp was 0.9 preoperatively and −2.5 postoperatively. Using a point Ap measurement of −0.5 or greater to define surgical failure, 28/30 (93%) of women were noted to have surgical cure on follow-up. Site-specific rectocele repair augmented with dermal allograft is associated with high cure rates and minimal complications. It recreates normal anatomic support and is easily adapted into current surgical procedures for rectocele repair.

Incidence of recurrent cystocele after anterior colporrhaphy with and without concomitant transvaginal needle suspension

OBJECTIVE Our purpose was to compare the recurrent cystocele rate after anterior colporrhaphy versus anterior colporrhaphy performed in conjunction with transvaginal needle bladder neck suspension. STUDY DESIGN A retrospective chart review of all patients undergoing anterior colporrhaphy with and without needle bladder neck suspension over a 3-year period was conducted. Preoperatively all patients had symptomatic anterior vaginal wall relaxation. Patients undergoing concomitant needle suspension procedures had genuine stress incontinence. Twenty-seven patients underwent anterior colporrhaphy alone, and 40 patients underwent anterior colporrhaphy with needle suspension. Demographic data including age, parity, menopausal status, and use of estrogen replacement was collected for each group. The recurrence rate of anterior vaginal wall relaxation was determined for each group by reviewing standardized postoperative office notes. RESULTS There was no significant difference in the duration of follow-up between the two groups (13.2 months in the anterior repair group vs 13 months in the anterior repair-needle suspension group). However, a significant difference in recurrent cystocele rates was found between the two groups (7% [2/ 27] in the anterior repair group compared with 33% [13/40] in the anterior repair-needle suspension group, p < 0.01). CONCLUSION The incidence of recurrent cystocele is significantly higher after anterior colporrhaphy with concomitant needle bladder neck suspension compared with anterior colporrhaphy alone. This difference may be related to the vaginal retropubic dissection at the time of transvaginal needle bladder neck suspension resulting in an iatrogenic paravaginal defect or denervation of the anterior vaginal wall.

Uterine preservation during surgery for uterovaginal prolapse: a review

The traditional surgical treatment for uterovaginal prolapse has been vaginal hysterectomy. For many reasons, women may request uterine preservation at the time of prolapse surgery. The purpose of this paper is to review the medical literature pertaining to the role of uterine preservation during reconstructive surgery for uterovaginal prolapse. A MEDLINE search of literature in the English language (1966 to current) was carried out using the keywords ‘hysterectomy’, ‘hysteropexy’, ‘uterine preservation’, ‘uterine suspension’ and ‘uterovaginal prolapse.’ Fourteen articles primarily addressing the surgical repair of uterovaginal prolapse with uterine preservation were included in this review. Papers primarily addressing other forms of pelvic organ prolapse, incontinence or obliterative procedures were excluded. Existing procedures and their clinical outcomes were reviewed. The current literature suggests that uterine preservation during surgery for uterovaginal prolapse may be an option in appropriately selected women who desire it; prospective, randomized trials are needed to corroborate this.

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR–mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation. Mol Cancer Ther; 13(2); 410–25. ©2013 AACR.