Sutent
Sutent
I decided to open a new thread here as this is a very interesting option so it will be better if we collect all the related info in a separate thread - add you comments and related experiences here. The drug is promising and active but it's problem is a rapid action when it works and associated bleeding - as I remember there were a few deaths in every trial and they decided not to use it in case when there are big deep visceral or brain tumors or mets when sudden bleeding is a problem - may be tehy have enough experience now to find it. So for everyone who is going to start is - read all the related info on the PubMed.gov from the past trials in the other diseases - it was done a few so try to obtain the full text and read its side effects and symptoms. Also there are proceedings of the last ASCO annual 2007 meeting avail. on their web-site and there might be some fresh info too - it is not getting ported on the Pubmed so they do not overlap.
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Fictional
A new SUTENT thread is a good idea.
We like the fact that it is fairly well tolerated and as mentioned, it's tumor necrosis effect is relatively fast. John Goldberg told us Avastin response was assessed at 14 weeks, whereas SUTENT was assessed at 6 weeks. We also like the fact that is a pill that one can take at home.
Based on the Tsuda paper, ASPS seems to have plenty of VEGF, and its vascularity also suggests it would be a good target. I saw in one abstract in the ASCO meeting that suggested SUTENT and Nexavar are not completely overlapping so that if a person doesn't respond to one, they may potentially be a candidate to the other drug.
SUTENT received expedited approval this year for GIST and kidney cancers last year. One forum that shared info about side effects of SUTENT was this one for the kidney cancer http://www.cancercompass.com/message-bo ... 6833,0.htm.
We like the fact that it is fairly well tolerated and as mentioned, it's tumor necrosis effect is relatively fast. John Goldberg told us Avastin response was assessed at 14 weeks, whereas SUTENT was assessed at 6 weeks. We also like the fact that is a pill that one can take at home.
Based on the Tsuda paper, ASPS seems to have plenty of VEGF, and its vascularity also suggests it would be a good target. I saw in one abstract in the ASCO meeting that suggested SUTENT and Nexavar are not completely overlapping so that if a person doesn't respond to one, they may potentially be a candidate to the other drug.
SUTENT received expedited approval this year for GIST and kidney cancers last year. One forum that shared info about side effects of SUTENT was this one for the kidney cancer http://www.cancercompass.com/message-bo ... 6833,0.htm.
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Fictional
We just missed the SUTENT trial at the U of WA, but we got it in off label use. Our UW oncologist Doug Hawkins has been very nice about talking to John Goldberg at DF, and they both agreed on the dosing and plan. At times it's hard to really know who is doing what. We plan on returning to Boston for surgery regardless.
We initially had sticker shock at the pharmacy when 28 day supply of pills came to $5800 (we had been warned about this), and out Premera denied its coverage, but Doug had just obtained approval through Premera for another patient on appeal (as long as PET was done to follow response), and a day later we heard Premera had agreed to pay for 3 courses (4 weeks). Hurrah! On another patient forum we heard SUTENT was available through his local Walgreens. Pretty wild.
'K' has just started and has no side effects, although steady state apparently takes 7-10 days. Interestingly, though, for GIST tumors, reduction in PET responses could be seen in as early as 4 days.
Our plan is for 4 weeks on 2 weeks off, then 4 weeks on and repeat the PET on the last day. We heard the PET scan showed an SUVmax of 2.3 - not sure how that compares with others here with alveolar. There was no clear uptake anywhere except her primary, but PET is not as sensitive as CT, of course.
We initially had sticker shock at the pharmacy when 28 day supply of pills came to $5800 (we had been warned about this), and out Premera denied its coverage, but Doug had just obtained approval through Premera for another patient on appeal (as long as PET was done to follow response), and a day later we heard Premera had agreed to pay for 3 courses (4 weeks). Hurrah! On another patient forum we heard SUTENT was available through his local Walgreens. Pretty wild.
'K' has just started and has no side effects, although steady state apparently takes 7-10 days. Interestingly, though, for GIST tumors, reduction in PET responses could be seen in as early as 4 days.
Our plan is for 4 weeks on 2 weeks off, then 4 weeks on and repeat the PET on the last day. We heard the PET scan showed an SUVmax of 2.3 - not sure how that compares with others here with alveolar. There was no clear uptake anywhere except her primary, but PET is not as sensitive as CT, of course.
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Fictional
You are right that high resolution CT / MRI is more sensitive for small metastases. I think where the PET scans are more valuable are in revealing their responsivity to different chemotherapeutic agents and to some extent, the activity of the tumor. With a slow growing tumor, the PET responsiveness may tell you much earlier whether a chemo or other regimen is having an effect. It would take much longer for a size difference to be registered. At least some studies with different types of cancers (not ASPS, because it's too rare) have shown that PET activity predicts chemoresponsivenss. In our case, Premera was only willing to cover the SUTENT because a baseline PET could be used to assess responsiveness...we won't continue on the drug if her tumor doesn't respond.
Also the SUPmax has at least at higher levels, correlated with the aggressiveness of a tumor (it is less accurate at lower levels, for instance distinguishing benign from low grade malignant tumor). That can also be valuable as different tumor sites may vary in their SUPmax. It a subtotal resection is being considered, it may also tell a surgeon what area of the tumor is more aggressive.
Combination PET/CT promises to be even more sensitive, I think.
Also the SUPmax has at least at higher levels, correlated with the aggressiveness of a tumor (it is less accurate at lower levels, for instance distinguishing benign from low grade malignant tumor). That can also be valuable as different tumor sites may vary in their SUPmax. It a subtotal resection is being considered, it may also tell a surgeon what area of the tumor is more aggressive.
Combination PET/CT promises to be even more sensitive, I think.
ASPS SUVmax
What was the baseline SUVmax before the treatment started? We do not really have an information reg. PET readings for the big ASPS primaries (we already know that small lung mets are not picked up by the PET).
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Fictional
I requested a CD copy of the PET, but haven't gotten that yet to compare it to her MRI, but based on the report alone, it said that the superior part of the mass was SUVmax 2.3 (sorry, I guess I wrote SUPmax before).
I am wondering whether they didn't get a complete PET signal throughout the mass, but maybe that would become clearer after I actually look at the PET films. Based on the report, I almost thought only part of it had signal, be we also have the confounding factor of a hematoma (the mass was initially 4 cm in its largest extent by ultrasound, but after 4 core needle biopsy passes under u/s the MRI suggested it might be as large as 6 cm in its largest extent).
At least through Seattle Childrens imaging, it's been easy to request CD copies of everything. After CT or MRI, we usually just need to wait 5 minutes or so after the scan and then we can leave with the CD. I then burn a copy and send it to our other doctors at Dana Farber. I think this may be a good idea if available to some of you - the reports are not good enough for doctors or surgeons to make decisions.
In one case, the DF doctors raised questions about something on 'K''s films that the Seattle doctors didn't. Also, although we aren't radiologists, we found it easier to understand what they were talking about after we had looked at the films ourselves. The format we get the CDs in is "DICOM" and these seem to play on any computer CDrom drive.
Hope this might help someone -
'F'
I am wondering whether they didn't get a complete PET signal throughout the mass, but maybe that would become clearer after I actually look at the PET films. Based on the report, I almost thought only part of it had signal, be we also have the confounding factor of a hematoma (the mass was initially 4 cm in its largest extent by ultrasound, but after 4 core needle biopsy passes under u/s the MRI suggested it might be as large as 6 cm in its largest extent).
At least through Seattle Childrens imaging, it's been easy to request CD copies of everything. After CT or MRI, we usually just need to wait 5 minutes or so after the scan and then we can leave with the CD. I then burn a copy and send it to our other doctors at Dana Farber. I think this may be a good idea if available to some of you - the reports are not good enough for doctors or surgeons to make decisions.
In one case, the DF doctors raised questions about something on 'K''s films that the Seattle doctors didn't. Also, although we aren't radiologists, we found it easier to understand what they were talking about after we had looked at the films ourselves. The format we get the CDs in is "DICOM" and these seem to play on any computer CDrom drive.
Hope this might help someone -
'F'
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Fictional
I just wanted to update this forum about our experience after our first Sutent cycle.
Our 10 year old daughter has tolerated this medication remarkably well. She has had only very mild symptoms (occasional brief pains from the tumor, sore tongue 1 day only, occasional loose BMs, no diarrhea) and her energy level has been excellent. I have been following her lab studies and she had mild drops in her wbc count (ANC from 4400 to 1300...stable) and brief platelet decrease (lowest 100K) has now returned to normal. She's on 37.5 mg, but she's also big for a 10 year old (5 feet, 95 lbs). She just takes 2 capsules at bedtime, and we were able to get Premera to cover three 4-week courses of medication (hurrah!). She will finish this first cycle in 5 days.
Base on what we can see, there is some tumor shrinkage. She first noted some changes at only day 7 of the medication, and there seemed to be a somewhat abrupt decrease in size early in her 2nd week, but that may have plateaued. If I made a guesstimate, I would think the part of the tumor we can see has reduced in volume by about 1/4. The tumor became flatter and the tissues were looser around it. Our daughter had also been using a topical anesthetic to help with itching, but she found that she doesn't need it anymore. We are thanking God for all of this, but also realize that we still don't know if it can shrink enough to help the surgeon resect it completely, but not also take healthy tissues (colon, urethra).
We also know that most of her tumor is "inside" and cannot be seen, so imaging will be the most reliable to know that we've had a good effect. Nevertheless, we were encouraged to find that other cancer-responders on Sutent (not ASPS, but renal cancer and GIST) had some similar time courses if they responded, and also some similar reports of pains or discomfort.
We'll have to be patient and wait until the end of her 2nd - 4 week course to do our re-imaging. I just wanted to share this because I know this could be valuable for others in this forum. Not everyone responds to Sutent, but ASPS, like renal CA and GIST are very vascular tumors. There have been some complete remissions even from diffuse metastatic disease (absolutely amazing), and some people have such mild side effects (like us) they have chosen to be on this medication non-stop. I know one woman who has been on it for 2 years. Some others who had no perceptible cancer after Sutent are stopping the medication and just monitoring to see if it comes back.
There have also been a few deaths with Sutent - and I think there may be more risk with brain mets (because the tumor may bleed), but I also know the drug is being investigated for some primary brain tumors. So the medication is not without risk. Also 'K' had an EKG and ECHO, and I assume clinicians are looking into the possibility of negative effects on the heart.
Sutent does have potential to help those with metastatic disease because it does go to lungs, liver, and brain. If there is a family history of non-smoking and cancer, there may also be a higher likelihood that your cancer will respond favorably to anti-angiogenesis medications like Sutent.
Blessings to you all, and please feel free to email if you have questions, 'F'
Our 10 year old daughter has tolerated this medication remarkably well. She has had only very mild symptoms (occasional brief pains from the tumor, sore tongue 1 day only, occasional loose BMs, no diarrhea) and her energy level has been excellent. I have been following her lab studies and she had mild drops in her wbc count (ANC from 4400 to 1300...stable) and brief platelet decrease (lowest 100K) has now returned to normal. She's on 37.5 mg, but she's also big for a 10 year old (5 feet, 95 lbs). She just takes 2 capsules at bedtime, and we were able to get Premera to cover three 4-week courses of medication (hurrah!). She will finish this first cycle in 5 days.
Base on what we can see, there is some tumor shrinkage. She first noted some changes at only day 7 of the medication, and there seemed to be a somewhat abrupt decrease in size early in her 2nd week, but that may have plateaued. If I made a guesstimate, I would think the part of the tumor we can see has reduced in volume by about 1/4. The tumor became flatter and the tissues were looser around it. Our daughter had also been using a topical anesthetic to help with itching, but she found that she doesn't need it anymore. We are thanking God for all of this, but also realize that we still don't know if it can shrink enough to help the surgeon resect it completely, but not also take healthy tissues (colon, urethra).
We also know that most of her tumor is "inside" and cannot be seen, so imaging will be the most reliable to know that we've had a good effect. Nevertheless, we were encouraged to find that other cancer-responders on Sutent (not ASPS, but renal cancer and GIST) had some similar time courses if they responded, and also some similar reports of pains or discomfort.
We'll have to be patient and wait until the end of her 2nd - 4 week course to do our re-imaging. I just wanted to share this because I know this could be valuable for others in this forum. Not everyone responds to Sutent, but ASPS, like renal CA and GIST are very vascular tumors. There have been some complete remissions even from diffuse metastatic disease (absolutely amazing), and some people have such mild side effects (like us) they have chosen to be on this medication non-stop. I know one woman who has been on it for 2 years. Some others who had no perceptible cancer after Sutent are stopping the medication and just monitoring to see if it comes back.
There have also been a few deaths with Sutent - and I think there may be more risk with brain mets (because the tumor may bleed), but I also know the drug is being investigated for some primary brain tumors. So the medication is not without risk. Also 'K' had an EKG and ECHO, and I assume clinicians are looking into the possibility of negative effects on the heart.
Sutent does have potential to help those with metastatic disease because it does go to lungs, liver, and brain. If there is a family history of non-smoking and cancer, there may also be a higher likelihood that your cancer will respond favorably to anti-angiogenesis medications like Sutent.
Blessings to you all, and please feel free to email if you have questions, 'F'
Two new articles reg. Sunitinib
Two new articles reg. Sunitinib specific toxicity profile are published in the last issue of JCO - Volume 25, Issue 23 August 10, 2007
Tumor Lysis Syndrome After Treatment of a Gastrointestinal Stromal Tumor With the Oral Tyrosine Kinase Inhibitor Sunitinib
Philip J. Saylor and Tony R. Reid
JCO Aug 10 2007: 3544–3546.
and
Reversible Posterior Leukoencephalopathy Syndrome Induced by Sunitinib
German Martín, Lorena Bellido, and Juan Jesus Cruz
JCO Aug 10 2007: 3559. [Full Text] [PDF]
Tumor Lysis Syndrome After Treatment of a Gastrointestinal Stromal Tumor With the Oral Tyrosine Kinase Inhibitor Sunitinib
Philip J. Saylor and Tony R. Reid
JCO Aug 10 2007: 3544–3546.
and
Reversible Posterior Leukoencephalopathy Syndrome Induced by Sunitinib
German Martín, Lorena Bellido, and Juan Jesus Cruz
JCO Aug 10 2007: 3559. [Full Text] [PDF]
Sunitinib - surgery time frame?
There are the issues complicating operative intervention in the setting of multitargeted tyrosine kinase inhibitors such as Sunitinib - based on its ability to inhibit several targets involved in angiogenesis and endothelial cell proliferation it can interfere with the healing process. I know that surgery is avoided for 1 month after discontinuation of the Avastin - is a time frame for Sunitinib and followed surgery already found?
There is a new relevant article on a Pubmed
Consolidative renal cell carcinoma metastatectomy for partial response after multitargeted tyrosine kinase inhibitor therapy.
http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum
if anyone have an access to the full text of this article-would you please comment on this issue here.
There is a new relevant article on a Pubmed
Consolidative renal cell carcinoma metastatectomy for partial response after multitargeted tyrosine kinase inhibitor therapy.
http://www.ncbi.nlm.nih.gov/sites/entre ... d_RVDocSum
if anyone have an access to the full text of this article-would you please comment on this issue here.
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Fictional
Hi again, Olga. When we spoke to our doctors at Dana Farber, they had operated after Sutent within as few as 3 days. Usually 1 month is recommended after radiation. We specifically asked about that when we were in Boston. There is a study in a different tumor (GIST?) that found there are no increased complications operating within a few days after discontinuing Sutent, and so that is what the surgeons told us at DF (at least if I understood that right).
It is also difficult to rely only on publications because of the lag time and the selection process (who decides to submit findings for publication, etc.). When we spoke to one of the scientists involved in the development of Sutent, she said that George Demetrios (at DF) had the greatest world clinical experience with that medication - because of their large collection of GIST cases there (GI vascular sarcoma). That is why we have been particularly interested in hearing what our DF doctors have to say.
The other thing to factor in re: the side effects and responses to medication are what the primary and mets are located. Some of the GI side effects with Sutent in GIST can also be due to the fact the tumor metastasizing throughout the intestines. If you look at some of the effects of Sutent on other vascular tumors (like HCC http://media.pfizer.com/files/investors ... 060407.pdf, see slide 21 out of 68), it is no wonder that some tumor lysis syndromes occasionally occur. Tumor lysis syndromes occur when the kill of tumor cells is so quick and the burden of tumor so high, that problems like too much protein flooding the bloodstream at once, happens. If a person's tumor burden is low, I would think that would be less likely.
Based on both literature and behind the literature talk to clinicians and a few scientists we know in the business, Sutent...if a particular person's tumor is responsive, has a generally low side effect profile and quickest tumor reduction effect. Some investigators have also suggested that Sutent and Nexavar are overlapping, but distinct...so that if tumors fail to respond to one, they respond to another. Some tumors initially respond to Sutent, but then stop - leading docs to switch meds then. There have been some believed complete clinical remissions, but to my knowledge this has only been with metastatic renal CA. If the tumor responds so that no more is seen with imaging, doctors don't know how long they should still give it. I have seen some continuing for a few to 6 months after no evident disease, and then just trying to check by follow-up scans.
One problem knowing how to make decisions with ASPS is that our numbers are too small. When I was looking into all the literature, I did include other vascular tumors similar in pathology because vascularization is present as an early pathological finding for ASPS. When looking at candidate medications, renal CA also came to mind because in children, some of these tumors are actually caused by the same TFE3 fusion as ASPS: http://ajp.amjpathol.org/cgi/reprint/159/1/179.pdf
In our decision-making process, we also liked the possibility that an anti-angiogenesis factor may reduce the formation of new metastases if they had recently seeded. This again because it seems that the formation of new vessels is important for the setting down of new metastases. Sutent's effects are not solely due to anti-angiogenesis, though. It is not well known exactly why cancer cells apoptose or die.
We have now finished out our first course and 'K' is planning to start school as planned after Labor Day, when, God willing, she'll start her second 4-week course. It looks like some favorable effects are still being seen, but as mentioned, we really have to look at imaging, and that they are not planning until the end of the second cycle.
Blessings to you all, 'F'
It is also difficult to rely only on publications because of the lag time and the selection process (who decides to submit findings for publication, etc.). When we spoke to one of the scientists involved in the development of Sutent, she said that George Demetrios (at DF) had the greatest world clinical experience with that medication - because of their large collection of GIST cases there (GI vascular sarcoma). That is why we have been particularly interested in hearing what our DF doctors have to say.
The other thing to factor in re: the side effects and responses to medication are what the primary and mets are located. Some of the GI side effects with Sutent in GIST can also be due to the fact the tumor metastasizing throughout the intestines. If you look at some of the effects of Sutent on other vascular tumors (like HCC http://media.pfizer.com/files/investors ... 060407.pdf, see slide 21 out of 68), it is no wonder that some tumor lysis syndromes occasionally occur. Tumor lysis syndromes occur when the kill of tumor cells is so quick and the burden of tumor so high, that problems like too much protein flooding the bloodstream at once, happens. If a person's tumor burden is low, I would think that would be less likely.
Based on both literature and behind the literature talk to clinicians and a few scientists we know in the business, Sutent...if a particular person's tumor is responsive, has a generally low side effect profile and quickest tumor reduction effect. Some investigators have also suggested that Sutent and Nexavar are overlapping, but distinct...so that if tumors fail to respond to one, they respond to another. Some tumors initially respond to Sutent, but then stop - leading docs to switch meds then. There have been some believed complete clinical remissions, but to my knowledge this has only been with metastatic renal CA. If the tumor responds so that no more is seen with imaging, doctors don't know how long they should still give it. I have seen some continuing for a few to 6 months after no evident disease, and then just trying to check by follow-up scans.
One problem knowing how to make decisions with ASPS is that our numbers are too small. When I was looking into all the literature, I did include other vascular tumors similar in pathology because vascularization is present as an early pathological finding for ASPS. When looking at candidate medications, renal CA also came to mind because in children, some of these tumors are actually caused by the same TFE3 fusion as ASPS: http://ajp.amjpathol.org/cgi/reprint/159/1/179.pdf
In our decision-making process, we also liked the possibility that an anti-angiogenesis factor may reduce the formation of new metastases if they had recently seeded. This again because it seems that the formation of new vessels is important for the setting down of new metastases. Sutent's effects are not solely due to anti-angiogenesis, though. It is not well known exactly why cancer cells apoptose or die.
We have now finished out our first course and 'K' is planning to start school as planned after Labor Day, when, God willing, she'll start her second 4-week course. It looks like some favorable effects are still being seen, but as mentioned, we really have to look at imaging, and that they are not planning until the end of the second cycle.
Blessings to you all, 'F'
Re: Sutent
All--
We recently returned from a tour de doctors, as Anthony likes to call it. We visited Schrump @ NCI, Berstein @ NCI and Maki @ MSK. All were extremely helpful and comfortable. Schrump had some trials open, but didn't think any were fit for Anthony. Schrump also mentioned that Anthony's primary tumor should not be removed as it's not our big problem...his lung mets are. Berstein spoke to us about Nelfinafir and another drug that is similar to Sutent. We then visited Maki. He mentioned that we should immediately get on Sutent. So that's what we are going to try. We are excited to try it and measure progress which we will update here.
We also asked if radiation could be performed while taking the drug and Maki mentioned that we should try Sutent first so there may be better responses with all the tumors.
Thank you again for all your help!
We recently returned from a tour de doctors, as Anthony likes to call it. We visited Schrump @ NCI, Berstein @ NCI and Maki @ MSK. All were extremely helpful and comfortable. Schrump had some trials open, but didn't think any were fit for Anthony. Schrump also mentioned that Anthony's primary tumor should not be removed as it's not our big problem...his lung mets are. Berstein spoke to us about Nelfinafir and another drug that is similar to Sutent. We then visited Maki. He mentioned that we should immediately get on Sutent. So that's what we are going to try. We are excited to try it and measure progress which we will update here.
We also asked if radiation could be performed while taking the drug and Maki mentioned that we should try Sutent first so there may be better responses with all the tumors.
Thank you again for all your help!
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Fictional
Re: Sutent
For anyone who's interested, the slide presentation from Italy describing some ASPS responses to Sutent can be seen here: http://www.asco.org/ASCO/Abstracts+&+Vi ... ctID=33650
An updated abstract is included in the slide presentation. 2 out of 4 had partial responses, 1/4 stable disease, and 1/4 progression disease. The benefits still seem only mild though - with significant patient variability in response and some tumors responding more than others. Metastases showing some effect included lung and soft tissue. In one patient, a liver, spleen, and bone mets progressed extensively on Sutent - this patient may have had a high disseminated tumor load. Longest response - patient A who continues to respond after 10 months.
Met seems highly activated in these patients.
An updated abstract is included in the slide presentation. 2 out of 4 had partial responses, 1/4 stable disease, and 1/4 progression disease. The benefits still seem only mild though - with significant patient variability in response and some tumors responding more than others. Metastases showing some effect included lung and soft tissue. In one patient, a liver, spleen, and bone mets progressed extensively on Sutent - this patient may have had a high disseminated tumor load. Longest response - patient A who continues to respond after 10 months.
Met seems highly activated in these patients.
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Fictional
Re: Sutent
Hi, a friend sent this to me this morning: http://clincancerres.aacrjournals.org/c ... /1096?etoc
It's the paper about Sutent and ASPS from the Italian group. I'm trying to get the full length article.
Alveolar soft part sarcoma (ASPS) is a rare, chemoresistant soft tissue sarcoma. ASPS harbors the t(17-X) (p11.2;q25) translocation, resulting in the ASPACR1-TFE3 fusion protein, causing MET autophosphorylation and activation of downstream signaling. The tumor vascular pattern prompted us to use sunitinib malate (SM), a tyrosine kinase inhibitor with antiangiogenic properties.
Experimental Design: Since July 2007, five patients with progressive metastatic ASPS have been treated with continuous SM 37.5 mg/d on a named basis. Four patients are evaluable for response. In four cases, cryopreserved material was available. Upstream and downstream targets of receptor tyrosine kinase (RTK) pathways, as well as mechanisms of activation, were investigated by biochemical profiles, including human phospho-receptor RTK antibody arrays and immunoprecipitation/Western blotting, molecular analyses, immunohistochemistry, and fluorescence in situ hybridization analyses.
Results: After 3 months, two patients had RECIST (response evaluation criteria in solid tumor) partial response, as well as positron emission tomography response and subjective improvement. One had a RECIST stable disease. One progressed and stopped treatment. One patient is still responding after 12 months. The upstream analysis showed activation of all the platelet-derived growth factor receptor (PDGFR) family members, as well as epidermal growth factor receptor, MET families, and RET. Vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) were activated only in one case. The downstream target analysis showed strong activation of phosphatidylinositol 3-kinase/AKT, extracellular signal-regulated kinase 1/2, and mTOR and its targets (S6K and S6). The absence of any upstream mTOR effector deregulation and the presence of RTK cognate ligands support an autocrine-paracrine activation loop mechanism.
Conclusion: SM may have antitumor activity in ASPS, possibly through a mechanism involving PDGFR and RET. The role of MET, epidermal growth factor receptor, and mTOR, as well as PDGFR inhibition, needs to be further explored.
Best wishes, 'F'
It's the paper about Sutent and ASPS from the Italian group. I'm trying to get the full length article.
Alveolar soft part sarcoma (ASPS) is a rare, chemoresistant soft tissue sarcoma. ASPS harbors the t(17-X) (p11.2;q25) translocation, resulting in the ASPACR1-TFE3 fusion protein, causing MET autophosphorylation and activation of downstream signaling. The tumor vascular pattern prompted us to use sunitinib malate (SM), a tyrosine kinase inhibitor with antiangiogenic properties.
Experimental Design: Since July 2007, five patients with progressive metastatic ASPS have been treated with continuous SM 37.5 mg/d on a named basis. Four patients are evaluable for response. In four cases, cryopreserved material was available. Upstream and downstream targets of receptor tyrosine kinase (RTK) pathways, as well as mechanisms of activation, were investigated by biochemical profiles, including human phospho-receptor RTK antibody arrays and immunoprecipitation/Western blotting, molecular analyses, immunohistochemistry, and fluorescence in situ hybridization analyses.
Results: After 3 months, two patients had RECIST (response evaluation criteria in solid tumor) partial response, as well as positron emission tomography response and subjective improvement. One had a RECIST stable disease. One progressed and stopped treatment. One patient is still responding after 12 months. The upstream analysis showed activation of all the platelet-derived growth factor receptor (PDGFR) family members, as well as epidermal growth factor receptor, MET families, and RET. Vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) were activated only in one case. The downstream target analysis showed strong activation of phosphatidylinositol 3-kinase/AKT, extracellular signal-regulated kinase 1/2, and mTOR and its targets (S6K and S6). The absence of any upstream mTOR effector deregulation and the presence of RTK cognate ligands support an autocrine-paracrine activation loop mechanism.
Conclusion: SM may have antitumor activity in ASPS, possibly through a mechanism involving PDGFR and RET. The role of MET, epidermal growth factor receptor, and mTOR, as well as PDGFR inhibition, needs to be further explored.
Best wishes, 'F'