Multiple VEGF Family Members are Simultaneously Expressed in Ovarian Cancer: a Proposed Model for Bevacizumab Resistance

Multiple VEGF Family Members are Simultaneously Expressed in Ovarian Cancer: a Proposed Model for Bevacizumab Resistance.:


Curr Pharm Des. 2012 May 14;

Abstract
Objective Insight into the expression of multiple vascular endothelial growth factor (VEGF) family members can support the implementation of anti-angiogenic therapy. This study aimed to assess VEGF family member expression in ovarian cancers and related omental metastases.

Methods Tissue microarrays encompassing 270 primary cancers and 112 paired metastases were immunostained for VEGF-A, VEGF-B, VEGF-C and VEGF-D. Staining intensities were categorized as absent, weak, moderate or strong. Expression was related to clinicopathological characteristics and survival.

Results Immunohistochemical positivity (defined as moderate or strong expression) was observed for VEGF-A in 90%, VEGF-B in 4%, VEGF-C in 41% and VEGF-D in 55% of the primary ovarian cancers. ....... VEGF family member expression showed no independent prognostic significance in multivariate survival analysis.

Conclusion VEGF-A, VEGF-C and VEGF-D are widely and often simultaneously expressed in ovarian cancer, which may contribute to bevacizumab resistance. Measuring their expression could support a rational, individualized choice of anti-angiogenic therapy and might be of predictive value. Studies are warranted to determine whether combinatorial analysis of VEGF family member expression can be used to predict anti-angiogenic drug efficacy.

VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5

VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5

Objective 
To evaluate the role of VEGF-dependent Claudin 5 production for the development of ascites via influencing endothelial permeability in peritoneal tissue of ovarian cancer patients.

Conclusion 
VEGF induces ascites in ovarian cancer patients. This instance happens due to increased peritoneal permeability, caused by downregulation of the tight junction protein Claudin 5 in the peritoneal endothelium.

A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites

A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites

Objective 
The recombinant fusion protein, aflibercept binds and neutralizes vascular endothelial growth factor (VEGF) A, B and placental growth factor (PlGF). Aflibercept inhibits ascites formation and reduces tumor burden in an ovarian cancer model. This open-label, single-arm, multicenter phase II study assessed the efficacy and safety of aflibercept in patients with advanced chemo-resistant epithelial ovarian cancer and symptomatic malignant ascites.

Methods 
Patients who required ≥3 previous paracenteses at 1-4 paracenteses per month received intravenous aflibercept 4mg/kg every 2weeks. The primary endpoint was repeat paracentesis response rate (RPRR), with response defined as at least a two-fold increase in time to repeat paracentesis compared with the baseline interval.

Results 
Ten out of 16 enrolled patients achieved a response; the RPRR was 62.5% (95% CI 35.4%–84.8%). Aflibercept was considered effective based on a hypothesis that the RPRR was ≥60%. Median time to repeat paracentesis was 76.0 (95% CI 64.0–178.0) days, which was 4.5 times longer than the baseline interval (16.8days). Median progression-free survival was 59.5 (95% CI 41.0–83.0) days. Twelve patients experienced adverse events considered related to aflibercept treatment including hypertension (7 patients), headache, anorexia, and dysphonia (3 patients each). Two patients experienced Grade 3/4 treatment-related adverse events (Grade 3 hypertension and weight loss in one patient, Grade 3 intestinal perforation in one patient).

Conclusion 
Aflibercept 4mg/kg every 2weeks was effective at controlling malignant ascites, reducing the interval between repeat paracenteses. The safety profile was consistent with that reported for anti-VEGF agents.

ELC : Investigator Insights: VEGF and VEGFR Inhibitors in Gynecologic Malignancies

  Blogger's Note: requires registration

CME expires 2013

Investigator Insights: VEGF and VEGFR Inhibitors in Gynecologic Malignancies

Preclinical and clinical investigations provide a strong rationale for the use of angiogenesis inhibitors in ovarian primary peritoneal/fallopian tube cancer, and a large variety of angiogenesis inhibitors are in late stages of development. Drs. Thomas Herzog and Robert Burger discuss VEGF and VEGFR inhibitors including emerging data from clinical trails, management of toxicities and the future direction of this field.

updated - link to full free paper: Review: Therapeutic strategies in epithelial ovarian cancer (references clear cell ovarian)

 Blogger's Note: numerous references to clear cell ovarian cancer as per Japanese historical ovarian cancer research



direct link to pdf file 

 "In summary, it appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas are, in fact, secondary.

Previous data support the view that serous tumors develop from the fimbria, the most distal part of the fallopian tube, endometrioid and clear cell tumors from endometrial tissue passing through the fallopian tube resulting in endometriosis and mucinous and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact to the peritoneum.

Although the data suggesting that epithelial ovarian carcinoma arises in extra-ovarian sites and involves the ovaries secondarily are compelling, low- and high-grade serous carcinomas involve the ovaries and other pelvic and abdominal organs, such as the omentum and mesentery, much more extensively than the fallopian tubes. Similarly, although endometrioid carcinomas develop from endometriosis, which frequently involves multiple sites in the pelvis, these tumors are usually confined to the ovaries.

It is likely that the predisposition for
growth in the ovary is multifactorial but the precise reasons for this are unknown."

abstract: (Avastin) Bevacizumab-Associated Fistula Formation in Postoperative Colorectal Cancer Patients - adverse events

Blogger's Note: adverse events are worth noting albeit other types of cancers; full text of paper would be required to properly assess the conclusions of this particular study

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Conclusions

Bevacizumab is the most common antiangiogenesis agent used for treatment of metastatic CRC. Previous adverse events associated with bevacizumab treatment include venous thromboembolism, poor wound healing, and spontaneous bowel perforation. In this report, late postoperative development of fistulas occurred relatively soon after initiation of bevacizumab and usually spontaneously resolved with cessation of bevacizumab treatment. Based on the timing of fistula development relative to operation and initiation of bevacizumab, fistulas are likely secondary to bevacizumab therapy rather than postsurgical complications. Bevacizumab-induced fistulas occur in a small, but significant proportion of CRC patients and must be recognized early.

abstract: Intracranial hemorrhage in patients with cancer treated with bevacizumab (Avastin) : the Memorial Sloan-Kettering experience

Background: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor approved for recurrent glioblastoma (GBM), metastatic breast, colorectal and non-small-cell lung cancers (NSCLC). There has been a potentially increased risk of intracranial hemorrhage (ICH) in patients receiving bevacizumab.

Methods: We retrospectively identified patients with ICH who received bevacizumab between 1 January 2001 and 10 January 2009.

Results: We identified 1024 patients with ICH, 4191 patients who received bevacizumab and 12 (0.3%) who met both our criteria. There were eight women and four men with a median age of 66 years. Primary cancers were ovarian (n = 3), NSCLC (n = 3), colon (n = 1), angiosarcoma (n = 1) and GBM (n = 4). Intracranial tumors were present in 9 of the 12 patients; the remaining three (25%) had no evidence of intracranial pathology. Two hundred and fifty-seven patients with these same primary pathologies and brain tumors were treated with bevacizumab; ICH was seen in nine (3.7%), which was comparable to the 3.6% frequency seen in comparable patients not receiving bevacizumab.

Conclusions: ICH with bevacizumab treatment in this population is rare and does not appear to increase its frequency over the baseline rate of ICH in a comparable population. Most bevacizumab-related ICH occurs into central nervous system tumors but spontaneous hemorrhages were seen.

Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor

ConclusionThalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort.

The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab (Avastin)

Results 

Thirty-eight patients were included. All patients were heavily pre-treated with a median of five prior regimens. ..... The VEGF serum level decreased during treatment in all patients. A low pre-treatment VEGF level was predictive to response. 

Conclusions

Single agent bevacizumab has activity in ovarian cancer patients. Pre-treatment serum VEGF seems to have predictive value.

The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab (Avastin)

CONCLUSIONS:
Single agent bevacizumab has activity in ovarian cancer patients. Pre-treatment serum VEGF seems to have predictive value.

Abstract/full access; TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients

Abstract (provisional)

Background

Angiogenesis appears to play an important role in ovarian cancer. Vascular endothelial growth factor (VEGF) has recently been implicated as a therapeutic target in ovarian cancer. The tissue inhibitor of metalloproteinase 1 (TIMP-1) is involved in tissue invasion and angiogenesis. The application of serum TIMP-1 and VEGF to monitor primary therapy and predict clinical outcome of patients with ovarian cancer is unclear.

Initial Assessment, Surveillance, and Management of Blood Pressure in Patients Receiving Vascular Endothelial Growth Factor Signaling Pathway Inhibitors -- Maitland et al. 102 (9): 596 -- JNCI Journal of the National Cancer Institute

Box 1. Summary recommendations

1. Conduct and document a formal risk assessment for potential cardiovascular complications before vascular endothelial growth factor signaling pathway (VSP) inhibitor treatment. The assessment should include standardized blood pressure measurements (two separate sessions are suggested) and thorough history and examination to assess specific cardiovascular risk factors, and directed laboratory studies as indicated. (Table 2 summarizes the risk factors.) The purpose of this evaluation is to guide the physician and patient in determining the appropriate intensity of monitoring and control of blood pressure elevations. This provides an important opportunity to address comorbidities that through more attentive management could help prolong the patient's life and support more aggressive anticancer therapy.
   
2. Recognize that preexisting hypertension will be common in cancer patients and should be identified and addressed before initiation of VSP inhibitor therapy. Given the suspected importance of pretreatment intervention in the management of VSP inhibitor–induced blood pressure elevations, properly collected, objective, office measurements or more thorough evaluations for isolated office hypertension (also known as "white coat hypertension") should guide the risk assessment rather than patient and/or physician speculation and dismissal.
   
3. Actively monitor blood pressure throughout treatment with more frequent assessments during the first cycle of treatment. The first cycle is typically when the bulk of the blood pressure elevation is expected to occur and when most patients unexpectedly present with elevations warranting treatment even in the absence of preexisting cardiovascular risk factors.
   
4. The goal for hypertension control in patients receiving VSP inhibitor therapy is a maximum blood pressure of 140/90 mmHg, and efforts to reach this goal should begin before initiation of VSP inhibitor therapy. The recommendation for a goal of maintaining blood pressure less than 140/90 mmHg is based on prudence and consistency with general guidelines. As per the risk stratification considerations, targets should be adjusted lower for patients with multiple preexisting risk factors for adverse consequences of high blood pressure. For example, for patients with diabetes and/or chronic kidney disease, a goal blood pressure of less than 130/80 mmHg is the current public health recommendation.
   
5. Manage blood pressure elevations aggressively to avoid the development of complications associated with excessive/prolonged elevations. Management requires attention to proper agent selection, dosing, and scheduling of follow-up to ensure efficacy and to control adverse effects of the antihypertensive agent. The panel suggests that at any time, if the oncologist or responsible medical team member has any difficulty in helping the patient progress to the goal blood pressure of 140/90 mmHg, consultation with the local hypertension specialist (cardiologist, nephrologist, endocrinologist, or certified hypertension specialist) should be obtained promptly.

full free access: COMMENTARY Initial Assessment, Surveillance, and Management of Blood Pressure in Patients Receiving Vascular Endothelial Growth Factor Signaling Pathway Inhibitors

"Inhibiting angiogenesis is an effective approach to cancer therapy, but it has been associated with cardiovascular toxic effects. At times, adverse events such as hypertension and heart failure have led to treatment cessation and even life-threatening consequences. Cancer patients have often been excluded from studies of cardiovascular disease, and patients with clinically significant cardiovascular disease have been excluded from studies of new cancer therapies. Consequently, the capacity for determining the incidence or prevalence of cardiovascular toxic effects of anticancer agents and to determine their optimal management has been limited. Oncologists and cardiovascular medicine specialists have increasingly recognized that the prevention and management of these toxic effects is important for these potentially life-sustaining anticancer agents to benefit the greatest possible number of patients."
 
Box 1. Summary recommendations

VEGF in ovarian cancer from ResearchVEGF.com - Genentech website

define:VEGF

Definitions of VEGF on the Web:

* Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels. ...
en.wikipedia.org/wiki/VEGF

* Stimulates the growth of blood vessels.
www.vibrantskinspa.com/ingredients.asp

* A protein that is secreted by oxygen-deprived cells, such as cancerous cells. VEGF stimulates new blood vessel formation, or angiogenesis, by binding to specific receptors on nearby blood vessels, encouraging new blood vessels to form.
www.alnylam.com/Global/glossary.php

* A protein that binds to receptors on epithelial cells and promotes their growth, stimulates angiogenesis, and increases permeability of the ...
linkinghub.elsevier.com/retrieve/pii/S1546144003000231

* Substances produced by diseased tissues or rapidly growing tissues which play an important role in the formation of abnormal blood vessels and ...
www.uhn.ca/Focus_of_Care/KNC/DKJ_Eye_Centre/glossary.asp

* VEGF promotes venous, venule, artery, arteriole and capillary health by providing the essential cofactors for repairing and restoring damaged vessels.
www.bioproducts.co.nz/Default.asp

Rapid Development of Hypertension and Proteinuria with Cediranib, an Oral Vascular Endothelial Growth Factor Receptor Inhibitor -- Robinson et al. 5 (3): 477 -- Clinical Journal of the American Society of Nephrology

Conclusions: Cediranib induced a rapid but variable rise in BP within 3 days of initiation in most patients. Proteinuria was common and also developed rapidly. The rapid development of hypertension suggests that acute inhibition of VEGF-dependent vasodilation might explain the BP rise with VEGF inhibitors. Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients.

Intraperitoneal VEGF Inhibition Using Bevacizumab: A Potential Approach for the Symptomatic Treatment of Malignant Ascites?

"THE NECESSITY FOR CLINICAL TRIALS EVALUATING BEVACIZUMAB TREATMENT IN PATIENTS WITH MALIGNANT ASCITES
Based on the preclinical and clinical data outlined above, we strongly suggest that the efficacy and safety of the i.p. application of bevacizumab for the treatment of malignant ascites be assessed in stringently designed clinical studies. Bevacizumab is generally well tolerated and has an acceptable toxicity profile consisting primarily of hypertension and proteinuria. Other rare but important adverse effects, however, include delayed wound healing, arterial thrombosis, and bleeding [118]. Finally, a potentially serious adverse effect of bevacizumab is gastrointestinal perforation and, although comparably infrequent, this potentially life-threatening complication has generated significant clinical interest. Overall, gastrointestinal perforation was found to be an uncommon but well-documented side effect of treatment in the phase III trials of bevacizumab, as well as in subsequent surveillance trials, with a reported incidence of 1%–2% [106, 107, 109, 119]. Though strong evidence identifying specific risk factors is lacking, investigators have urged caution when treating patients with known bowel implants or a large tumor burden, prior radiation, and recent surgery or bowel obstruction [106, 119, 120]."