Her 2 and Her 3 signalling and Dr M Moasser

[Ellie F]

Hi everyone
I have been reading the research from Dr Moasser about the relationship between her 2 and her 3 and the possible explanation of why herceptin alone may not be enough to contain bc.

He believes that it will be possible to eradicate advanced bc if we can get this combination right and 3 days (yes days) of no signalling kills the cells!!

Wondered if anyone had more info or knew if there were any trials yet?

He seems to be advocating short high doses of lapatinib with rapamycin, a drug I understand is used to stop rejection of transplanted organs.

Hope I have got the essence of this correct. If not maybe Lani, Steph or someone will chime in.

Ellie

Please Ellie, could you give a link?

He has had (and might still have) small trials at UCSF of high dose intermittent Tykerb. I don't know about with the other drug. You could check the UCSF trial website for further information.

Maybe that clinical trial can be good http://www.clinicaltrials.gov/ct2/sh...pamycin&rank=3

[Ellie F]

Here is a link
http://ww5.komen.org/Abstracts.aspx?...ycle=2007-2008

Ellie

Thank you Ellie, its called "Research Grants Awarded", does it mean that Doctor Moasser has become this grant?

A drug that targets HER2, called Tykerb, now is being used to test this new dosing strategy. In the clinical trial, women with advanced breast cancer are being treated with large, intermittent dosages of the drug instead of with daily, lower-dosage treatment. The larger dosage should more effectively kill tumor cells, Moasser, says. Breaks in treatment are intended to limit side effects.

The Phase 1 clinical trial is open to women with HER2-positive breast cancers that continue to grow after prior treatment with standard therapies.

http://clinicaltrials.gov/ct2/show/NCT00544804

[Lani]

for those confused by unregistered's post--lapatinib and tykerb are one and the same drug.

Hope this helps!

[Lani]

at SABCS they reported on combining herceptin and lapatinib as well as herceptin and pertuzumab, the latter also blocking her3. 2009 SABCS also reported on neratinib.

There are several trials on now I believe with mTor inhibitors, of which rapamycin was the template drug--there are other mTor inhibitor like everolimus which are already FDA approved (for keeping vascular stents open)

For about five years not, researcher have realized that the trick will probably be getting the right combination of targeted therapies for the patient's individual tumor characteristics (which oncogenes and signalling pathways are particularly driving its growth and spread)

Finding the best test to determine which pathways are the critical ones and then giving the right drugs seems to be the way of the future, but a way which clinical trials as currently designed are ill-designed for.

Better ways to test for minimal residual disease (or more bone marrow testing to see if treatments were effective, or better ctc testing) may help.

Lani, so can it really work - what Dr Moasser does?

[Ellie F]

Thanks Lani
I feel really frustrated that we POSSIBLY have the cure or at least a long term management strategy YET we still seem as far away as ever.So far it really seems hit and miss, with more toxic chemos which I believe equips the cancer cells to create greater survival strategies! Is it not time now medicine has reached this consensus that they get together and develop trials that either support or disprove this hypothesis?
One question I have, does bone marrow sampling always indicate the prescence of tumour cells?

Sorry to go on!!

Ellie

[Lani]

this goes back to studies done on mice by Dr Kent Osborne back about 6or 7 years ago. He blocked egfr, her2 and her3 and the tumors went away and didn't recur for the life of the mouse even when ER was not blocked on those tumors that were er+

I think it will depend on an individual tumor's driving signalling pathways as well as the tumor's response to the drugs--some tumors secrete a large mucin molecule that acts like an oil slick around the cell and keeps the drug from getting to the receptors. Other tumors lack PTEN or other parts of the signalling pathway or have a truncated her2 so herceptin can't get at the extracellular domain to bind to the receptor.

I think we are getting close to having enough drugs to mix and match to keep her2+ bc under control if not cure it. However we are now nowhere near being able to discover for any one particular patient's tumor which combination will be the right one for them. I think we can catch up relatively quickly to be able to find a way to predict that magic tailor-made combination if government funding were to be increased (it is now being decreased), research emphasis were placed on this problem and people let their computers be used for the hours they are down to share the computing power with researchers off-hours. We are closer than we have ever been and we are understanding a subtype of breast cancer (her2+) better than we have understood any other type. I hope the trends in medicine do not prevent individualized treatments, as there seems to be a consensus that this will be necessary.

We need the will to have the way (like the goal in 1960 of going to the moon in the next 5-8 years)

[chrisy]

Lani,
you are right on target, so to speak!

[Lani]

No Ellie. It is a better predictor of minimal residual disease, future recurrence than CTCs and when her2+ the bone marrow cells (DTCs) are much better able to predict recurrence than when her2-. It seems her2+ patients rarely have her2- DTCs in their bone marrow, but her2-s may have her2+ cells, especially after they have been treated with antihormonals or chemos (ie, their cancer tries to switch to increase her signalling in order to survive the onslaught of chemos)

Remember these cells may be very slowly dividing and more difficult to eradicate with chemo therefore and may represent the cancer stem cells responsible for recurrences, if you adhere to the stem cell theory of breast cancer, which i do.

Lani, could you answer please:
so,
1) Blockade of her3 is not a cure?
2) Can any researcher block her3 for now?
3) What do you think about M. Moasser's study with extremaly dosage of lapatinib?
Thank you

[Lani]

blocking her2 is not necessarily a cure for all her2+ breast cancers for the Ireasons I listed above and others, such as upregulation of EGFR, IGFR1 etc.

Blocking her2 and her3 or blocking egfr, her2 and her3 may be a cure for a subgroup of her2+ breast cancers especially done so quickly that the tumor does not have time to find another signalling pathway to get around the blockade.

THere are drugs which block her3 which are used by researchers and in some clinical trials. Dr Ulrich, who got the AACR lifetime achievement award for herceptin (he did the work at Genentech) believes blocking her3 will be the most beneficial and effective way to work towards curing her2+ breast cancer.

Am not quite sure what you mean re Dr. Moasser's work, but if you are referring to giving the doses more intermittently rather than continuously to decrease the side effects, I would have to reread any articles to form an opinion. Obviously it would be nice for patient to go for longer periods without diarrhea!!

[Lani]

here is a quick bibliography of Dr Moasser's articles on the topic (and closely related ones):


The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics.
Amin DN, Campbell MR, Moasser MM.
Semin Cell Dev Biol. 2010 Dec;21(9):944-50. Epub 2010 Sep 9.
PMID: 20816829 [PubMed - in process]
Related citations
3.
Resiliency and vulnerability in the HER2-HER3 tumorigenic driver.
Amin DN, Sergina N, Ahuja D, McMahon M, Blair JA, Wang D, Hann B, Koch KM, Shokat KM, Moasser MM.
Sci Transl Med. 2010 Jan 27;2(16):16ra7.
PMID: 20371474 [PubMed - indexed for MEDLINE]
Related citations
4.
HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy.
Campbell MR, Amin D, Moasser MM.
Clin Cancer Res. 2010 Mar 1;16(5):1373-83. Epub 2010 Feb 23.
PMID: 20179223 [PubMed - indexed for MEDLINE]
Related citations
5.
A phase I study of a 2-day lapatinib chemosensitization pulse preceding nanoparticle albumin-bound Paclitaxel for advanced solid malignancies.
Chien AJ, Illi JA, Ko AH, Korn WM, Fong L, Chen LM, Kashani-Sabet M, Ryan CJ, Rosenberg JE, Dubey S, Small EJ, Jahan TM, Hylton NM, Yeh BM, Huang Y, Koch KM, Moasser MM.
Clin Cancer Res. 2009 Sep 1;15(17):5569-75. Epub 2009 Aug 25.
PMID: 19706807 [PubMed - indexed for MEDLINE]Free Article
Related citations
6.
MRI methods for evaluating the effects of tyrosine kinase inhibitor administration used to enhance chemotherapy efficiency in a breast tumor xenograft model.
Aliu SO, Wilmes LJ, Moasser MM, Hann BC, Li KL, Wang D, Hylton NM.
J Magn Reson Imaging. 2009 May;29(5):1071-9.
PMID: 19388114 [PubMed - indexed for MEDLINE]
Related citations


9.
A phase II trial of erlotinib in combination with bevacizumab in patients with metastatic breast cancer.
Dickler MN, Rugo HS, Eberle CA, Brogi E, Caravelli JF, Panageas KS, Boyd J, Yeh B, Lake DE, Dang CT, Gilewski TA, Bromberg JF, Seidman AD, D'Andrea GM, Moasser MM, Melisko M, Park JW, Dancey J, Norton L, Hudis CA.
Clin Cancer Res. 2008 Dec 1;14(23):7878-83.
PMID: 19047117 [PubMed - indexed for MEDLINE]Free PMC ArticleFree text
Related citations
10.
HER-2-directed, small-molecule antagonists.
Arkin M, Moasser MM.
Curr Opin Investig Drugs. 2008 Dec;9(12):1264-76. Review.
PMID: 19037833 [PubMed - indexed for MEDLINE]
Related citations
11.
A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition.
Torbett NE, Luna-Moran A, Knight ZA, Houk A, Moasser M, Weiss W, Shokat KM, Stokoe D.
Biochem J. 2008 Oct 1;415(1):97-110.
PMID: 18498248 [PubMed - indexed for MEDLINE]Free Article
Related citations

13.
The epidermal growth factor receptor family: biology driving targeted therapeutics.
Wieduwilt MJ, Moasser MM.
Cell Mol Life Sci. 2008 May;65(10):1566-84. Review.
PMID: 18259690 [PubMed - indexed for MEDLINE]
Related citations
14.
The HER family and cancer: emerging molecular mechanisms and therapeutic targets.
Sergina NV, Moasser MM.
Trends Mol Med. 2007 Dec;13(12):527-34. Epub 2007 Nov 5. Review.
PMID: 17981505 [PubMed - indexed for MEDLINE]
Related citations
15.
Improved tumor vascular function following high-dose epidermal growth factor receptor tyrosine kinase inhibitor therapy.
Moasser MM, Wilmes LJ, Wong CH, Aliu S, Li KL, Wang D, Hom YK, Hann B, Hylton NM.
J Magn Reson Imaging. 2007 Dec;26(6):1618-25.
PMID: 17968965 [PubMed - indexed for MEDLINE]
Related citations

17.
Targeting HER proteins in cancer therapy and the role of the non-target HER3.
Hsieh AC, Moasser MM.
Br J Cancer. 2007 Aug 20;97(4):453-7. Epub 2007 Jul 31. Review.
PMID: 17667926 [PubMed - indexed for MEDLINE]Free PMC ArticleFree text
Related citations
18.
Targeting the function of the HER2 oncogene in human cancer therapeutics.
Moasser MM.
Oncogene. 2007 Oct 11;26(46):6577-92. Epub 2007 May 7. Review.
PMID: 17486079 [PubMed - indexed for MEDLINE]
Related citations
19.
The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis.
Moasser MM.
Oncogene. 2007 Oct 4;26(45):6469-87. Epub 2007 Apr 30. Review.
PMID: 17471238 [PubMed - indexed for MEDLINE]
Related citations
20.
Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3.
Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM.
Nature. 2007 Jan 25;445(7126):437-41. Epub 2007 Jan 7.
PMID: 17206155 [PubMed - indexed for MEDLINE]
Related citations

[Lani]

not sure if this is what you are referring to, which is pulsing lapatinib or other drugs working vs the her family to increase tumor vasculature before delivery of cytotoxic chemotherapy drugs.

J Magn Reson Imaging. 2007 Dec;26(6):1618-25.
Improved tumor vascular function following high-dose epidermal growth factor receptor tyrosine kinase inhibitor therapy.
Moasser MM, Wilmes LJ, Wong CH, Aliu S, Li KL, Wang D, Hom YK, Hann B, Hylton NM.

Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA. mmoasser@medicine.ucsf.edu
Abstract
PURPOSE: To determine if inhibitors of the human growth factor receptor (HER) family can be used to enhance tumor vascular permeability and perfusion and optimize the efficacy of cytotoxic chemotherapeutics. Poor tumor vascular function limits the delivery and efficacy of cancer chemotherapeutics and HER family tyrosine kinases mediate tumor-endothelial signaling in both of these compartments.

MATERIALS AND METHODS: BT474 human breast cancer tumors were established in mice and the biologic effects of the HER tyrosine kinase inhibitor (TKI) gefitinib on tumor vascular function was determined by dynamic contrast-enhanced MRI (DCE-MRI), and on tumor vascular architecture and perfusion by immunofluorescence microscopy.

RESULTS: A brief dose of gefitinib enhances the antitumor activity of paclitaxel in vivo but not in cell culture, suggesting that its chemoenhancing activity involves the in vivo microenvironment. A brief high dose of gefitinib induces a decrease in endothelial transfer constant (Kps) and a concomitant increase in tumor fractional plasma volume (fPV). These changes are accompanied by a rapid reduction in tumor volume, likely due to decreased tumor edema, and modestly improved tumor vascular architecture and perfusion on microscopy.

CONCLUSION: These data suggest that HER family TKIs have the potential to optimize the tumor microenvironment for delivery of cytotoxic chemotherapeutics.

(c) 2007 Wiley-Liss, Inc.
PMID: 17968965

[Ellie F]

Lani-just wanted to say many thanks for keeping us so well informed.

What I seem to have gathered so far is that it is thought that there are many sub-groups within her2 bc (let alone all the other types).At present we do not have sophisticated assessment tools for us to be able to determine all of these sub types and even less idea which combination of drugs will be effective (assuming that we have discovered enough drugs to treat all sub types!) The result seems to be pick and mix of chemos for advanced breast cancer (and some early stage).
I remember a famous onc from MSKCC talking about needing to use good scientific analysis with a mathematical model to determine individual treatment regimes. Why are we still so far away from this???

Ellie