Angiogenesis

 Laurl at ONS 

Welcome to the ONS Hot Topic Chats! Today’s expert is Paula Muehlbauer, who will be talking with us about any and all questions you have regarding Angiogenesis. Paula is experiencing technical issues from her computer so I will be typing her answers for her - she and I are in telephone contact right now -so you can feel free to ask your questions, I’ll type for Paula. To get started, where are you from?

 oncnurse 

Massachusetts

 jill 

Des Moines, Iowa

 Laurl at ONS 

Great, as you know I’m typing for Paula now. This is Paula talking! Welcome.

 Laurl at ONS 

Do you have any specific questions or would you like to start with an overview?

 jill 

I didn't have any specific questions, an overview would be wonderful.

 Laurl at ONS 

Ok, then let's start.

 Laurl at ONS 

Angiogenesis is a normal process, for physiologic functions such as fetal development, wound healing, growth and development, and menses.

 Laurl at ONS 

Usually angiogenesis is maintained by a tight balance of activators and inhibitors.

 Laurl at ONS 

However in tumor angiogenesis, that balance is shifted.

 Laurl at ONS 

This leads to a cascade of irregular molecular and cellular events.

 Laurl at ONS 

So what does this mean exactly?

 Laurl at ONS 

What this means is because that balance is upset, tumor angiogenesis (abnormal angiogenesis) can be stimulated.

 Laurl at ONS 

Interestingly, normal tissues then will supply small undetectable tumors with necessary oxygen, nutrients and waste removal.

 Laurl at ONS 

Tumor endothelial cells may divide up to 50 times more frequently than normal tissue endothelial cells.

 Laurl at ONS 

These tumor ECs (endothelial cells) are activated by the release of growth factors such as vascular endothelial growth factor (VEGF) fibroblast growth factor (FGF) and platelet-derived growth factor.

 Laurl at ONS 

These growth factors are released in response to various stimuli such as secreted proteins, hypoxia, hypoglycemia, and mechanical stress.

 Laurl at ONS 

Genetic mutations such as the loss of tumor-suppressor gene function can cause a decrease in angiogenesis inhibitors.

 Laurl at ONS 

Also, mutations in the RAS oncogene may increase VEGF expression (and therefore help grow tumors).

 Laurl at ONS 

Does any of this make sense?

 jill 

yes, very nice explanation

 oncnurse 

Yes, makes sense!

 Laurl at ONS 

Do you use antiangiogenic drugs in your setting?

 jill 

Yes, I work on an inpatient oncology floor and we are seeing more and more of

 Laurl at ONS 

Have you had issues with side effects? What have you been giving?

 jill 

We have seen some skin rashes with Sutent and Nexavar, but overall have not seen many side effects.

 Laurl at ONS 

So Sutent and Nexavar are actually what are known as multikinase inhibitors. So they DO target the VEGF pathway but they also target EGFR pathway (epidermal growth factor) so that is why you are seeing the rash, because think of where epidermal cells are - skin and lining GI tract - so that is why you see rash - its interfering with that pathway.

 Laurl at ONS 

Avastin is the one true antiangiogenic - it targets only the VEGF pathway. Thalidomide and Revlimid work on angiogenesis as well but the exact mechanism of action is not completely known.

 Laurl at ONS 

Do you give either of these drugs?

 jill 

So, Erbitux would be another EGFR?

 Laurl at ONS 

Yes and EGFR inhibitor.... but EGFR can induce angiogenic growth factors as well, such as VEGF... isn't that confusing!?

 jill 

Yes, we give Avastin and it seems like we are seeing it used with different types of cancer.

 Laurl at ONS 

You are right- what are you giving it for?

 oncnurse 

Breast cancer

 Laurl at ONS 

Yes FDA approved for breast cancer

 jill 

Colon, Breast, Ovarian, Brain tumor

 Laurl at ONS 

Yes, that's interesting - it's being used in clinical trials for ovarian and brain tumors with reported decent results.

 Laurl at ONS 

Do you see any of the other side effects of Avastin?

 jill 

Can you explain the timing of administration of these medications when given with chemotherapy? Most of our oncologists want them given first, but some of them say it doesn't really matter.

 Laurl at ONS 

I'm not sure that it does matter...I know that in clinical trials Avastin was given after the chemotherapy.... I don't think it's been proven which is the right way to do it (like many protocols!)

 jill 

I have seen 1 patient with hypertension from Avastin, but have not seen any other serious complications.

 Laurl at ONS 

Hypertension is a common side effect - and should be controlled with oral antihypertensives. Anyone with uncontrolled HTN should not be on Avastin.

 Laurl at ONS 

Another serious potential side effect of Avastin are thrombotic events, like DVTs.

 Laurl at ONS 

Think about the growth factor it's affecting....vascular....

 Laurl at ONS 

Now with thalidomide...

 Laurl at ONS 

...it works differently, but as with Revlimid as well, patients must be on special programs with the pharm company to agree to consistent effective birth control and monthly pregnancy tests prior to getting their drug. This is due to the significant teratogenic effect of the drugs.

 Laurl at ONS 

Also with thalidomide you can see peripheral neuropathy, weight gain, sleepiness, constipation.

 Laurl at ONS 

And with Revlimid, you can see peripheral edema, and hematologic side effects like neutropenia, thrombocytopenia.

 Laurl at ONS 

FYI thalidomide and Revlimid are both oral drugs...

 Laurl at ONS 

...and education is crucial when these are prescribed re: safety, compliance, etc. since they are giving to themselves.

 jill 

What is the main difference between Revlimid and Thalidomide?

 Laurl at ONS 

Revlimid is a "sister analog" to thalidomide... reportedly it is more potent...they aren't as sure as with thalidomide of its teratogenic potential but because it’s an analog you must take all similar precautions.

 Laurl at ONS 

In terms of what Revlimid is given for: given for Multiple Myeloma and myelodysplastic syndrome (certain types) and thalidomide is also indicated for multiple myeloma.

 jill 

So, how do these drugs work if they work differently than Avastin?

 Laurl at ONS 

Well, remember VEGF is needed for fetal growth and development. So there is some thought that they inhibit (particularly thalidomide) VEGF but they are still just not 100% sure of their mechanism of action. Think of when thalidomide was associated with the malformed limbs of fetuses...the thinking is that it was the VEGF inhibition that causes this and didn't allow the limbs to grow to full potential.

 Laurl at ONS 

Revlimid has some immunomodulatory properties as well as antiangiogenic. It can affect inflammatory cytokines and inhibit cell proliferation.

 Laurl at ONS 

Cytokines are one of the molecules that are activators of VEGF synthesis.

 Laurl at ONS 

So this the thinking around Revlimid works.

 jill 

Makes sense!

 Laurl at ONS 

Glad it did- it can be very confusing because there is not one clear (single) mechanism of action for some of these drugs!

 Laurl at ONS 

Just so you know...the vasculature that surrounds tumors is different from normal vasculature.... not normal...

 Laurl at ONS 

...it is leaky, the basement membrane of the cell become broken down...

 Laurl at ONS 

...and the tubules are tortuous... so you can see how this can allow tumor cells to migrate.

 Laurl at ONS 

Tumor angiogenesis can inhibit apoptosis... (programmed cell death).

 oncnurse 

Have you seen infusion reactions with Avastin?

 jill 

No, knock on wood.... have not seen an infusion reaction with Avastin

 Laurl at ONS 

No, not really. Avastin is a humanized monoclonal (this means primarily of human origin) versus chimeric (part mouse/part human) or murine (all mouse) monoclonal so the potential for reactions is quite low.

 Laurl at ONS 

In JCO 2007 Memorial Sloan Kettering recommended that all Avastin can be infused at 0.5 ml/kg/min safety - that is, over 30 minutes or less - no prolonged initial infusion time.

 Laurl at ONS 

But remember, people can have allergic reactions to any drug - so prudent monitoring is always a good idea!

 Laurl at ONS 

Other questions?

 jill 

No, thank-you for this valuable information.

 Laurl at ONS 

My pleasure...

 Laurl at ONS 

Traditionally it was thought that only solid tumors were angiogenic...

 Laurl at ONS 

...but it’s been shown that hematologic malignancies are as well (makes sense, since multiple myeloma responds to Revlimid and thalidomide).

 Laurl at ONS 

Currently what investigators are looking at is how to measure the efficacy of these drugs. They are currently pretty much always given concurrent with traditional chemotherapy... or in the case of thalidomide and Revlimid, they are given with dexamethasone.

 Laurl at ONS 

Some providers do extend Avastin after chemotherapy ends...

 Laurl at ONS 

And thalidomide is given with melphalan and prednisone for Multiple myeloma too.

 oncnurse 

How can they tell if these drugs are working?

 Laurl at ONS 

Good question!

 Laurl at ONS 

Generally, traditionally we tell if they are working by using things like imaging modalities (CT, MRI).

 Laurl at ONS 

However with antiangiogenic agents because they work on the tumor vasculature but do not necessarily shrink the tumor (just choke of the blood supply) it may look like there is no response on traditional CT or MRI.

 Laurl at ONS 

So investigators are using either dynamic MRI (which is the rapid administration of gadolinium-based contrast followed by fact analysis of signal intensity) ultrasound, and variety of optical techniques. So it's possible to determine microvasculature during antiangiogenic therapy because patterns of MRI contract update correlate with tumor microvascular density.

 Laurl at ONS 

Also PET scans are being used because they can assess tumor metabolism or tumor blood flow or tumor blood volume.

 Laurl at ONS 

Good question!

 Laurl at ONS 

Please don't stop asking questions, but also when we are done, please take a moment to cut and paste this URL into your browser and take our very brief survey at the end of the chat-we'd love to hear what you think of these chats! The URL is http://research.zarca.com/k/RsTUTRsSTQsXYTVVsPsP

 Laurl at ONS 

This link will also show up on any of the transcripts from this series and you can take the survey at any time (once the transcript is posted to the ONS website).

 Laurl at ONS 

We have a couple more minutes - any last burning questions about angiogenesis?

 Laurl at ONS 

Well, if you are out of questions :-) then we can call it a day! Thank you so much for participating on this chat - I hope you have found this to be informative and helpful to your understanding of tumor angiogenesis.

 oncnurse 

Thank you for your information!

 jill 

Thank-you. I learned alot.

 Laurl at ONS 

Great! Please come to the next hot topic sessions - they are about Neutropenia - starting April 14th.

 alot 

hi