why her2neu tumors are able to metastasize more readily than her2- and scheme2 defeat

[Lani]

They have found that, although on different chromosomes, the worst her2+ tumors have coamplification of uPA, a substance which breaksdown the extracellular matrix which glues the body together in order to facilitate invasion of the breast cancer cells deeply and widely.

The degree of concordance is remarkable. They are developing an anti-uPA
drug and propose giving herceptin and uPA simultaneously.

The fascinating part of this article is that, in the original they discuss that it is now possible to do her2 and uPA testing on INDIVIDUAL TUMOR CELLS--either from a touch prep of the original tumor (they cut the tumor in half and touch it on a piece of "waxpaper" which on average produces 100 cells for examination, or they isolate Circulating tumor cells and can do the test for individual gene amplifications on just a single cell!

Proc Natl Acad Sci U S A. 2006 Nov 1; [Epub ahead of print] Links
uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues.

Meng S,
Tripathy D,et al
Cancer Immunobiology Center, Departments of Internal Medicine, Pathology, and Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390;
paper to follow...

[Lani]

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.
PMID: 17079488 [PubMed - as supplied by publisher]

[Bev]

Could this explain why some patients don't respond to Herceptin?

BB

[Lani]

I did not add that to the post--because I don't like to keep posting things which remind everyone that herceptin works in in the minority of patients (usually quoted as around 40%) it is given to.

I have had one other thought(actually two!)

Since herceptin needs to be stored in such a narrow range of temperatures and transported in airconditioned trucks, etc. Perhaps one variable determining whether herceptin works in patients (whether the dose they are given is maximally active) could be controlled for by putting a "smart" label on it which changes color if it ever is not at the right temperature! It costs so much to begin with, how much more could it add to the cost?

Will see if I can bring this to the attention of Genentech(if my friend will take me along to their next stockholders meeting), as well as the makers of Rituximab(for lymphoma), Gleevec (leukemia, GIST), and some of the monoclonal antibodies given for rheumatoid arthritis.

In the meantime, if you are paranoid, ask your infusion nurse how they store the Herceptin and if there are alarms on the refrigerators which go off when the temperature is STARTING to get outside the normal range and who the alarm goes to and how far away they live. From what I understand it is delivered in refrigerated trucks.

In addition, there is 43% variability in the pharmacokinetics of herceptin ie, that is the percentage of patients who metabolize it faster or slower than normal. In those patients, they have a greater(slower metabolism) or smaller(faster metabolism) level of the antibody in their blood than others. Perhaps the latter could benefit from taking it more often and the former could take it less often. The dosage and timing were set based on the average metabolism. Testing has only been done originally to set the dosage and when I have been told that it is doubted if insurance companies would want to pay for the testing (they are afraid of the cost and that some patients may need it more often) and the drug companies are not motivated as some patients may need it less often.

These two things may play very minor roles as it is clear that there are many pathways cancer uses to get around the inhibition of any one. Blocking uPA makes a lot of sense (read the full article if you can get it).

I hope the uPA blockers become available soon. This research came out of MDAnderson for those going there--ask about the progress of the uPA inhibitors.

[Lani]

The company making the copper-binding compound has entered into an agreement with another company making the uPA inhibitor--so here is the news:







XOMA to Humanize Attenuon’s Novel Anti-Cancer Antibody

Applying Human EngineeringTM Technology to Advance Antibody Targeting
Urokinase Plasminogen Activator System

************************************************** *****************

Berkeley and San Diego, CA – October 3, 2006 -- XOMA Ltd. (Nasdaq: XOMA) and
Attenuon, LLC today announced an agreement for XOMA to utilize its Human
EngineeringTM (HETM) technology to humanize a monoclonal antibody targeting the
urokinase plasminogen activator (uPA) system for the treatment of cancer. The uPA
system plays a central role in multiple pathways and processes related to tumor growth,
metastasis, and angiogenesis (the growth of new blood vessels that feed tumors).
Attenuon will pay XOMA an up-front fee, development milestones, and royalties.
Attenuon will retain all development and commercialization rights to the antibody.
Additional financial terms were not disclosed.

[Lani]

“We believe that the uPA system is a promising target for inhibiting tumor growth,
metastasis, and angiogenesis,” said Josh Distler, Attenuon’s chief operating officer. “We
are very excited about this antibody based on the strong preclinical data we have obtained.
Humanizing this antibody using XOMA’s HETM technology is an important milestone in
our effort to develop this potential new treatment option for cancer patients.”

“We are pleased to work with Attenuon to improve the medical and commercial potential
of their antibody candidate through our HETM technology.” said Jack Castello, XOMA’s
chairman of the board, president, and chief executive officer. “We view this agreement
as another step forward in establishing our HETM technology as the basis of a new and
potentially significant line of business for XOMA.”

Human EngineeringTM Technology
HETM technology is a clinically tested humanization technology intended for modifying
non-human antibodies to make them suitable for medical use in humans. XOMA’s
patented HETM technology is distinct from other humanization techniques and is
independent of CDR grafting. HETM technology is based on the conserved structure-
function relationships among antibodies and defines which amino acid residues in a non-
human antibody variable region are candidates for substitution. XOMA’s deliverables
under HETM agreements generally include four HETM antibodies provided in three months,
that have preserved binding, structure, and function and are approximately 95% human.

[Lani]

About Attenuon
Attenuon is a San Diego-based clinical-stage biopharmaceutical company developing a
new generation of cancer therapeutics. Attenuon’s compounds – two of which are
currently in Phase II clinical trials – are intended to target a broad range of tumors and
the blood vessels that feed their growth without affecting healthy cells. These drug
candidates have the potential to be effective against many types of cancer, produce few
side effects, and be suitable for long-term use. For more information, please visit the
company's website at www.attenuon.com.

About XOMA
XOMA is a leader in the discovery, development and manufacture of therapeutic
antibodies, with a therapeutic focus that includes cancer and immune diseases. XOMA
has royalty interests in RAPTIVA® (efalizumab), a monoclonal antibody product
marketed worldwide (by Genentech, Inc. and Serono, SA) to treat moderate-to-severe
plaque psoriasis, and LUCENTISTM (ranibizumab injection), a monoclonal antibody
product marketed worldwide (by Genentech and Novartis AG) to treat neovascular (wet)
age-related macular degeneration.

The company has built a premier antibody discovery and development platform that
includes access to seven of the leading commercially available antibody phage display
libraries and XOMA’s proprietary Human EngineeringTM and bacterial cell expression
(BCE) technologies. More than 45 companies have signed BCE licenses. XOMA’s
development collaborators include Lexicon Genetics, Inc., Novartis, and Schering-Plough
Corporation. With a fully integrated product development infrastructure, XOMA’s
product development capabilities extend from preclinical sciences to product launch. For
more information, please visit the company's website at www.xoma.com.