Creating work environments where people of all genders in gynecologic oncology can thrive: An SGO evidence-based review.

Equality, equity, and parity in the workplace are necessary to optimize patient care across all aspects of medicine. Gender-based inequities remain an obstacle to quality of care, including within the now majority women subspecialty of gynecologic oncology. The results of the 2020 SGO State of the Society Survey prompted this evidence-based review. Evidence related to relevant aspects of the clinical care model by which women with malignancies are cared for is summarized. Recommendations are made that include ways to create work environments where all members of a gynecologic oncology clinical care team, regardless of gender, can thrive. These recommendations aim to improve equality and equity within the specialty and, in doing so, elevate the care that our patients receive.

Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

The new classifications of ovarian, fallopian tube, and primary peritoneal cancer and their clinical implications.

The roles of histologic characterization and staging are to provide reproducible metrics for cancer classification with which to direct the most appropriate clinical care and to yield the most stable reliable system to allow both prospective and retrospective data analysis. Both the histologic and staging classifications of malignant ovarian/tubal/peritoneal cancers have recently changed. The World Health Organization sponsored a review and reclassification of the pathology of cancers of the ovaries, fallopian tubes, and peritoneum, and published these updates in 2014. In so doing, they codified the two-tiered grading system that has been in use in serous ovarian cancers for nearly a decade. In parallel, FIGO reviewed and updated the surgical staging system, applied to all histotypes of ovarian, tubal, and peritoneal cancers, also published in 2014. In both cases, the changes made are meant to encompass a better understanding of disease, but both have important merits and drawbacks. Changes in staging complicate analysis of retrospective data against current data. Though in some aspects controversial, the changes overall are meant to represent a better biologic understanding of disease that we hope will lead to an improvement in patient care and directed therapy.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours.

This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.

PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies.

Poly(ADP-ribose)polymerase inhibitors (PARPis) have shown promising activity in patients with BRCA1/2 mutation-associated (BRCA1/2(MUT+)) ovarian and breast cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of sporadic high-grade serous ovarian cancer, and cancers defective in DNA repair pathways, such as prostate, endometrial, and pancreatic cancers. Several PARPis are currently in phase 1/2 clinical investigation, with registration trials now being designed. Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers. Understanding more about the molecular abnormalities involved in BRCA-like tumors, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers, is critical to rapidly advancing the field of PARPi therapy and improve clinical outcomes.

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions.

BACKGROUND: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs). METHODS: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered. RESULTS: All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6-65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR. CONCLUSION: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.

Clinical implications of using molecular diagnostics for ovarian cancers.

In the era of morphologic diagnostics, any epithelial tumor on or involving the ovaries was presumed to come from and be strictly of ovarian origin, apart from the rare but clearly metastatic tumors. Thus, many women who might have had small fallopian tube primary cancers that rapidly extended on to or into the ovary were deemed to have ovarian cancer. Now, as we begin to better understand that there are different types of cancers of nonuterine Muellerian origin, we expand upon the morphologic to add the molecular characteristics. Morphomolecular characteristics are being applied to drive clinical advances including development and optimization of predictive and prognostic biomarkers, redefinition of historical controls, and consideration of novel clinical trial designs. Ovarian cancer, not a common cancer to start with, is now subdivided into types, making ever smaller clinical cohorts. The first studies evaluating tubo-ovarian Muellerian cancers of morphomolecular types have begun. Deleterious mutations in BRCA1 or 2 have been validated as the first new predictive and prognostic biomarker of the high-grade serous ovarian cancer type and polyADPribose polymerase inhibitors, the first targeted agents for this morphomolecular entity. Similar progress is developing in other tubo-ovarian cancer types. This new knowledge is driving the building of a structure-function-type relationship that is generating novel clinically applicable hypotheses for testing.

Inferior vena cava ultrasonography before general anesthesia cannot predict arterial hypotension in patients undergoing vascular surgery.

INTRODUCTION: Intraoperative hypotension (IH) is an independent predictor of mortality. Some experts have suggested that ultrasound measurement of the inferior vena cava (IVC) in spontaneous ventilation can predict IH. OBJECTIVE: To evaluate the capacity of ultrasound measures of IVC in spontaneous ventilation to predict episodes of IH after anaesthesia induction. PATIENTS AND METHODS: We studied 55 high-risk cardiac patients undergoing vascular surgery. The maximum (dIVCmax) and minimum (dIVCmin) diameter of the IVC were measured and the collapsibility index CI = (dIVCmax-dIVCmin)/dIVCmax was calculated prior to anaesthesia induction. Three definitions of IH were used: systolic blood pressure (SBP) less than 100 mmHg, mean arterial pressure (MAP) less than 60 mmHg, and a decrease in MAP greater than or equal to 30% compared to baseline. RESULTS: There were no significant differences in dIVCmax or in CI between patients presenting IH after anaesthesia induction and those who did not. ROC curves for dIVCmax showed an area under the curve of 0.55 (0.39-0.70), 0.69 (0.48-0.90), and 0.57 (0.42-0.73) and ROC curves for the CI were 0.62 (0.47-0.78), 0.60 (0.41-0.78) and 0.62 (0.47-0.78) for the 3 definitions of IH (<100 mmHg, MAP < 60 mmHg, and MAP ≥30% baseline), respectively. CONCLUSIONS: Ultrasound measurements of IVC in spontaneous ventilation are not good predictors of IH after anaesthesia induction in these patients. The optimal cut-off points show low specificity and moderate sensitivity for predicting IH.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

BACKGROUND: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. METHODS: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. RESULTS: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. CONCLUSION: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

Proteomics as a guiding tool for more effective personalized therapy.

Ovarian cancer remains the deadliest gynecological malignancy in the Western world and is most often diagnosed at a rarely curable late stage. Examination of protein end points has been employed as an investigative mechanism to guide targeted therapy and to stratify ovarian cancer. Proteomics allows characterization of the proteins and the associated protein and peptide modifications. This has given us insight into the perturbations of signaling pathways within tumor cells and has improved the discovery of new drug targets and possible prognostic indicators of outcome and disease response to therapy. Development of validated assays that survey the genetic and/or proteomic make-up of an individual tumor will add greatly to the histological classification of the tumor and may lead to different treatment approaches tailored to the unique expression pattern of each individual patient. It is anticipated that application of proteomics may bring to reality the clinical adoption of molecular stratification, e.g. not, 'is the gene overexpressed?', but 'is the pathway upregulated?' This will be successful if validated peptide biomarkers are applied for patient selection prospectively and with inclusion of preplanned biological correlates. These events will guide future directions of proteomics as a selector and as a validator and will guide how we integrate proteomics information daily into patient care and into selecting therapy of advanced and recurrent ovarian cancer and other cancers.

Ovarian cancer in the proteomics era.

Ovarian cancer presents a diagnostic challenge because of its subtle clinical presentation and elusive cell of origin. Two new technologies of proteomics have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of ovarian cancer: mass spectrometry and protein array analysis. Mass spectrometry can provide a snapshot of a proteome in time and space, with sensitivity and resolution that may allow identification of the elusive "needle in the haystack" heralding ovarian cancer. Proteomic profiling of tumor tissue samples can survey molecular targets during treatment and quantify changes using reverse phase protein arrays generated from tumor samples captured by microdissection, lysed and spotted in serial dilutions for high-throughput analysis. This approach can be applied to identify the optimal biological dose of a targeted agent and to validate target to outcome link. The evolution of proteomic technologies has the capacity to advance rapidly our understanding of ovarian cancer at a molecular level and thus elucidate new directions for the treatment of this disease.

Las medidas ecográficas de la vena cava inferior no predicen hipotensión arterial postinducción anestésica en pacientes tratados mediante cirugía vascular / Inferior vena cava ultrasonography before general anesthesia cannot predict arterial hypotension in patients undergoing vascular surgery

Introducción: La hipotensión arterial intraoperatoria (HIO) es un predictor independiente de mortalidad. Las medidas ecográficas de la vena cava inferior (VCI) en ventilación espontánea han sido propuestas como predictores de este evento.ObjetivoEvaluar la capacidad de las medidas ecográficas de la VCI en ventilación espontánea para predecir episodios de HIO postinducción anestésica. Pacientes y métodos: Estudiamos a 55 pacientes de alto riesgo cardíaco tratados mediante cirugía vascular. Previamente a la inducción anestésica se midió el diámetro máximo de la VCI (dVCImáx.), el diámetro mínimo (dVCImín.) y el índice de colapsabilidad (ICVCI=dVCImáx. – dVCImin.)/dVCImáx.). Se utilizaron 3definiciones de HIO: presión arterial sistólica menor de 100mmHg, presión arterial media (PAM) menor de 60mmHg o un descenso de la PAM mayor o igual al 30% respecto a la PAM basal. Resultados: No hubo diferencias significativas en el dVCImáx. ni en el ICVCI entre quienes presentaron HIO postinducción anestésica y quienes no. Las curvas ROC para el dVCImáx. mostraron un área bajo la curva de 0,55 (0,39-0,70); 0,69 (0,48-0,90) y 0,57 (0,42-0,73), mientras que para el ICVCI fueron de 0,62 (0,47-0,78); 0,60 (0,41-0,78) y 0,62 (0,47-0,78), para las definiciones de HIO de<100mmHg, PAM<60mmHg y descenso de la PAM ≥ 30%, respectivamente. Conclusiones: Las medidas ecográficas de la VCI en ventilación espontánea no son buenos predictores de HIO postinducción anestésica en estos pacientes. Los puntos de corte óptimos permiten predecir hipotensión con baja especificidad y moderada sensibilidad.(AU)

Introduction: Intraoperative hypotension (IH) is an independent predictor of mortality. Some experts have suggested that ultrasound measurement of the inferior vena cava (IVC) in spontaneous ventilation can predict IH.ObjectiveTo evaluate the capacity of ultrasound measures of IVC in spontaneous ventilation to predict episodes of IH after anaesthesia induction. Patients and methods: We studied 55 high-risk cardiac patients undergoing vascular surgery. The maximum (dIVCmax) and minimum (dIVCmin) diameter of the IVC were measured and the collapsibility index CI=(dIVCmax-dIVCmin)/dIVCmax was calculated prior to anaesthesia induction. Three definitions of IH were used: systolic blood pressure (SBP) less than 100mmHg, mean arterial pressure (MAP) less than 60mmHg, and a decrease in MAP greater than or equal to 30% compared to baseline. Results: There were no significant differences in dIVCmax or in CI between patients presenting IH after anaesthesia induction and those who did not. ROC curves for dIVCmax showed an area under the curve of 0.55 (0.39-0.70), 0.69 (0.48-0.90), and 0.57 (0.42-0.73) and ROC curves for the CI were 0.62 (0.47-0.78), 0.60 (0.41-0.78) and 0.62 (0.47-0.78) for the 3 definitions of IH (<100mmHg, MAP<60mmHg, and MAP ≥30% baseline), respectively. Conclusions: Ultrasound measurements of IVC in spontaneous ventilation are not good predictors of IH after anaesthesia induction in these patients. The optimal cut-off points show low specificity and moderate sensitivity for predicting IH.(AU)

L651582: a novel antiproliferative and antimetastasis agent.

L651582 (Merck Institute for Therapeutic Research, Rahway, NJ) is a novel carboxyamide-amino-imidazole compound originally developed as a coccidiostat (U.S. patent No. 4,590,201). We studied the inhibitory effects of this compound on cancer proliferation, adhesion, and motility in vitro and in vivo in a model of ovarian cancer progression. L651582 reversibly inhibited up to 60% of the autocrine motility factor-stimulated tumor cell motility and tumor cell adhesion to tissue culture plastic. Autocrine motility factor-stimulated phosphoinositide metabolism was reduced significantly by treatment of the cells with 3 microM L651582 (P = .022). Thymidine incorporation and clonogenic growth of A2058 human melanoma, MDA-MB-231 human breast cancer, OVCAR-3 human ovarian cancer, and 5R-transformed rat embryo fibroblast cell lines were inhibited 60%-80% by 1-10 microM L651582. Intraperitoneal injection of OVCAR-3 cells causes malignant ascites, peritoneal carcinomatosis, and serosal and visceral seeding that, if left untreated, are lethal to nude mice. Intraperitoneal L651582 markedly prolonged survival of nude mice heavily laden with ovarian cancer [mean survival time of treated group divided by mean survival time of control group = 220% (P less than .03)]. The apparent mechanism of action of L651582 is via inhibition of the receptor-mediated stimulation of effector enzymes utilizing guanine nucleotide-binding protein signal transduction, which thus makes L651582 a novel anticancer agent. L651582 should be considered for further clinical development.

Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer.

BACKGROUND: Paclitaxel (Taxol), a diterpene plant product that promotes tubulin polymerization, has documented activity against a number of solid tumors, including ovarian cancer and breast cancer. PURPOSE: Our purpose was to conduct a phase II clinical trial investigating the response of patients with advanced recurrent ovarian carcinoma to high-dose paclitaxel combined with granulocyte colony-stimulating factor (G-CSF). METHODS: A prospective phase II clinical trial of patients with advanced-stage, recurrent ovarian cancer was undertaken. Patients received 250 mg/m2 paclitaxel every 21 days; cycles were given on a rigid schedule; delays were permitted only for extreme circumstances. G-CSF at a dose of 10 micrograms/kg per day was given to ameliorate myelo-suppression. If a patient showed fever and neutropenia, G-CSF dosage was increased to 20 micrograms/kg per day so that paclitaxel dose intensity could be maintained. Patients were assessed for response every two cycles, and those with complete radiographic resolution of disease underwent peritoneoscopy. RESULTS: Forty-four patients were assessable for response. Twenty-one had a reduction in tumor volume greater than 50%, yielding an objective response rate of 48% (21 of 44 patients; 95% confidence interval, 32%-63%). Six (14%) of the 44 patients had complete radiographic resolution of disease; two of the six also had negative biopsy specimens and washings at peritoneoscopy. Age, number of prior regimens, and clinical platinum resistance did not influence response rate or ability to maintain dose intensity. Dose intensity was maintained at the targeted level for up to 14 consecutive cycles of therapy. CONCLUSIONS: We observed a 48% response rate with dose-intense paclitaxel for patients with advanced-stage, platinum-resistant, recurrent ovarian cancer. The response rate is higher than previously reported for paclitaxel at a lower dose in similar cohorts of patients treated without G-CSF. Comparison of phase II studies of paclitaxel suggests a dose-response relationship. Therapy with dose-intense paclitaxel and G-CSF should be considered for patients with advanced, platinum-refractory ovarian cancer.

Molecular insights into cancer invasion: strategies for prevention and intervention.

The diagnosis and treatment of solid tumors usually begins at a late stage when most patients already have occult or overt metastasis. Many years of cancer progression precede diagnosis of most solid tumors. Novel noncytotoxic therapeutics may be specially suited for administration during this interval. An important window of intervention can be defined as the period during which transition from a hyperproliferative state to acquisition of the capacity for invasion and metastasis occurs. Investigation of the molecular basis of invasion is uncovering strategies for delaying progression of preinvasive carcinoma and treatment of primary tumors and established metastasis. Although tumor cell invasion might not be rate limiting for the growth of metastasis, anti-invasive agents can block tumor angiogenesis and thereby indirectly block metastasis growth. Two classes of molecular anti-invasion targets exist: (a) cell surface and extracellular proteins, which mediate sensing, adhesion, and proteolysis; and (b) signal transduction pathways, which regulate invasion, angiogenesis, and proliferation. Both categories of targets yield treatment approaches that are now being tested in the clinic. Metalloproteinase inhibitors, such as BB94, are based on the recognition that metalloproteinases play a necessary role in invasion and angiogenesis. The orally active signal transduction inhibitor carboxyamidotriazole modulates non-voltage-gated calcium influx-regulated signal pathways and reversibly inhibits tumor invasion, growth, and angiogenesis. Blockade of invasion, angiogenesis, or cellular signal pathways is likely to generate a cytostatic, rather than a cytotoxic effect. Cytostatic therapy constitutes an alternative paradigm for clinical translation that may complement conventional cytotoxic therapy. For patients with newly diagnosed solid tumors, long-term cytostatic therapy could potentially create a state of metastasis dormancy or delay the time to overt relapse following cytotoxic agent-induced remission. Clinical toxicity and pharmacology using oral cytostatic agents in phase I trials and in adjuvant settings will provide an important foundation for the translation of this approach to the preinvasive carcinoma period.

Suramin inhibits laminin- and thrombospondin-mediated melanoma cell adhesion and migration and binding of these adhesive proteins to sulfatide.

Suramin is a polysulfonated drug with several biological activities including inhibition of binding of some growth factors to cells, inhibition of tumor cell growth, and of glycosaminoglycan metabolism. We report here that suramin also inhibits binding of the adhesive glycoproteins, thrombospondin and laminin, to immobilized sulfatide with 50% inhibitory doses of 220 and 470 micrograms/ml, respectively. Sulfated glycoconjugates on melanoma cells mediate spreading on thrombospondin by binding to the amino-terminal heparin- and sulfatide-binding domain. This domain is also required for chemotaxis on thrombospondin. We therefore examined the effect of suramin on human melanoma cell spreading and migration. Suramin at 50-400 micrograms/ml specifically inhibited G361 melanoma cell spreading on thrombospondin without affecting cell attachment. Suramin also inhibited spreading of A2058 melanoma cells on thrombospondin and laminin and partially inhibited cell attachment. However, suramin had no effect on G361 or A2058 cell attachment or spreading on fibronectin. Chemotaxis of A2058 and G361 melanoma cells to thrombospondin and laminin were also specifically inhibited by suramin, as was haptotaxis of A2058 melanoma cells to laminin. However, suramin only weakly inhibited haptotaxis of G361 melanoma cells to thrombospondin, which is not mediated by the amino-terminal domain, and did not inhibit haptotaxis to fibronectin. These results suggest a new mechanism for the observed antitumor activity of suramin based on its ability to inhibit interactions of tumor cells with laminin or thrombospondin in the extracellular matrix.

In vivo efficacy of a novel inhibitor of selected signal transduction pathways including calcium, arachidonate, and inositol phosphates.

Aberrant signal transduction has been implicated in malignant transformation, growth, and progression. This has led to the proposal to use inhibitors of signal transduction pathways to treat cancer. One approach to circumventing potential toxicity and improving efficacy would be to target pathways upon which cancer cells selectively depend. Pathways associated with the malignant process involve calcium fluxes, the release of arachidonic acid, and the generation of phosphoinositides. In this report, CAI (L651582, NSC 609974), a substituted carboxyamido-imidazole and novel inhibitor of these selected signal transduction pathways, inhibits anchorage-dependent and -independent growth in a large series of human cancer cell lines. CAI pretreatment of HT-29 human colon cancer and 5R ras-transfected rat embryo fibroblast cells inhibits the formation and growth of experimental pulmonary metastases in nude mice. Oral administration of CAI in PEG-400 vehicle arrests growth and metastasis of transplanted human melanoma and ovarian cancer xenografts. No significant gross or histological toxicity was observed at CAI doses yielding blood levels in the concentration range demonstrated to inhibit select signal transduction pathways in vitro. These data indicate the feasibility and demonstrate a potential selectivity and sensitivity of using specific signal transduction inhibitors for the experimental treatment of cancer.

Anchorage-independent growth-conferring factor production by rat mammary tumor cells.

Conditioned medium from cultures of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumor cells contain factors that resemble sarcoma growth factor and other transforming growth factors in biological activity but differ in their physical properties. The mammary tumor factors (MTF) are acid stable and heat and protease sensitive. They inhibit the binding of epidermal growth factor, but not insulin, to mouse embryonal carcinoma cells. MTF confers upon normal rat kidney and BALB/c-3T3 cells the ability to grow in soft agar. This effect is enhanced synergistically by high concentrations of fetal calf serum but not by epidermal growth factor. Anchorage-independent growth promotion, however, is not seen with normal mammary epithelial cells, although MTF is mitogenic for these cells as well as normal rat kidney cells, BALB/c-3T3 cells, and chick embryo fibroblasts in monolayer culture, MTF is not mitogenic for primary cultures of the tumor cells from which the factors are derived. Two major molecular weight species of MTF, eluting at Mr 6,000 and 65,000 to 70,000 on Bio-Gel P-100 columns, are present in acid-ethanol extracts of 7,12-dimethylbenz(a)anthracene- and nitrosomethylurea-induced rat mammary tumors. Transplantable tumors derived from primary 7,12-dimethylbenz(a)anthracene- or nitrosomethylurea-induced tumors have little or no MTF activity. These results demonstrate that different chemically induced rat mammary tumors contain transforming growth factor-like activities. Furthermore, it is possible that MTF is unnecessary for the maintenance of tumorigenicity, since some tumors contain no detectable MTF.

Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers.

Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-excitable calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. Inhibition of calcium influx and calcium-dependent events is a potential common mechanism underlying these effects of CAI. The cytostatic and antiangiogenic properties of CAI led to its development for clinical investigation. In a Phase I clinical trial open to patients with refractory solid tumors, 49 patients received p.o. administered CAI daily or every other day. Two oral formulations, PEG-400 CAI solution and a gelatin capsule containing CAI in PEG-400, were tested. All administered dosages of CAI yielded plasma concentration at or above the range demonstrated to be effective in inhibiting signaling and cancer progression in vitro and in preclinical models (1 microgram/ml, 2.3 microM). Toxicity of p.o. administered CAI most commonly consisted of dose-related grade 1-2 nausea, vomiting, and occasional anorexia. CAI administration at bedtime ameliorated gastrointestinal complaints in many patients; others required addition of simple antiemetic regimens, usually consisting of metoclopropamide or prochlorperazine. Gastrointestinal complaints were the cause for compliance-limiting toxicity at 175 mg/m2/day of the liquid formulation and 125 mg/m2/day of the gelatin capsule formation. Reversible and rare sensory axonal neuropathy (grade 3, 1 patient) and neutropenia (grade 4, 1 patient) were dose-limiting toxicities observed at the 330 mg/m2 every-other-day liquid CAI dose level. No evidence of cumulative end organ damage or central nervous system injury was observed. Disease stabilization and improvement in performance status was observed. Disease stabilization and improvement in performance status was observed in 49% of evaluable patients who had disease progression before CAI. Disease stabilization and associated improvement in performance status was seen in patients with renal cell carcinoma (7 months), pancreaticobiliary carcinomas (3, 5, and 5 months), melanoma (7 months), ovarian cancer (7 months), and non-small cell lung cancer (3 months). The recommended Phase II doses from this trial are 150 mg/m2/day in the liquid formation and 100 mg/m2/day in the gelatin capsule formation.

Structure-function analysis of signal and growth inhibition by carboxyamido-triazole, CAI.

Evidence is accumulating that calcium homeostasis and calcium-regulated events may be selectively important in generation and maintenance of the malignant phenotype. CAI, a carboxyamido-triazole with a halogenated benzophenone tail, is a novel inhibitor of receptor-operated calcium influx and arachidonic acid release which inhibits malignant proliferation, invasion, and metastasis. The focus of this investigation was structural analysis of CAI and to determine if the inhibition of calcium influx and arachidonic acid release by CAI and its antiproliferative activity were mediated through the same chemical domains. Four families of molecular modifications of the CAI parent were synthesized: (I) modification or substitution of the triazole ring; (II) removal of the substituted benzophenone tail; (III) dehalogenation or partial truncation of the benzophenone moiety; and (IV) removal of the triazole and altered substitutions of the benzophenone tail. Compounds were tested for the inhibition of calcium influx and arachidonic acid release and inhibition of proliferation and colony formation in soft agar using the malignant CHO line transfected with the m5 muscarinic receptor and the A2058 human melanoma cell line. Only CAI and Group I compounds inhibited stimulated calcium influx, arachidonic acid release, and proliferation. Linear regression analysis of the relationship of the 50% inhibitory concentration values for all compounds in inhibition of calcium influx and arachidonate release was statistically significant (r2 = 0.993). Similarly, a linear relationship was demonstrated between inhibition of calcium influx and inhibition of tumor cell proliferation (r2 = 0.971). Groups II-IV had minimal or no signal or growth inhibitory activity. This investigation provides the first evidence for a coordinate link between calcium influx, calcium-mediated arachidonic acid release, and malignant proliferation and metastasis and constitutes the initial analysis of structurally important domains of the CAI molecule.