A better antiangiogenic way to block tumor growth (prevents rebound)!!

[Lani]

A potentially better option to blocks tumors
30. April 2009 00:31

On the heels of dismaying reports that a promising antitumor drug could, in theory, shorten patients' long-term survival, comes a promising study by a Japanese team of researchers that suggests a potentially better option.
The study appears in the May 11 issue of the Journal of Experimental Medicine (online April 27).

Many cancer treatments work by disrupting the formation of new blood vessels that feed growing tumors. Agents that block a vessel-promoting factor called VEGF have shown promise in human clinical trials. But recent studies in mice show that when treatment stops, tumor growth rapidly resumes. Now, Yoshiaki Kubota and colleagues find that blocking a different molecule, called M-CSF, suppressed tumor growth even after treatment was stopped.

Kubota and his team compared the efficacy of inhibitors against M-CSF and VEGF in mice with a certain kind of bone tumor. Three weeks of anti-VEGF treatment suppressed tumor growth but, similar to other recent reports, the tumors bounced back when the drug treatment was curtailed. Tumor growth in mice on a similar regiment of an M-CSF inhibitor remained suppressed in the absence of drug.

Another distinction between the two inhibitors was the type of vessel growth that was blocked. Blocking VEGF prevented dangerous vessels from growing such as those that feed tumors. But it also stopped beneficial vessels from growing, such as those that help injured tissues heal. Blocking M-CSF, on the other hand, only impeded bad vessel growth.

Most likely, the anti–M-CSF treatment had a lasting effect because it resulted in damage to the scaffolding that surrounds cancerous vessels, robbing the tumors of the structural support they need to grow. Meanwhile, the scaffold of mice treated with anti-VEGF remained intact.

M-CSF levels soar in patients with osteosarcoma (a malignant bone cancer), breast cancer and prostate cancer, making these cancers potentially the most responsive to M-CSF-blocking drugs Whether or not other types of cancer rely more on M-CSF than on VEGF for their blood supply remains unknown.

http://www.rockefeller.ed

[Rich66]

Are there any anti-M-CSF chemos available?

[Lani]

It will not be a chemo ...it will either be a monoclonal antibody which will require infusion or perhaps a tyrosine kinase inhibitor, small molecular drugs which can be taken orally. The former are by their nature exquisitely specific, the latter because of similarities of tyrosine sites which get phosporylated in a lot of different participants in many signalling systems are sometimes "promiscuous" ie, having their effect on many different signalling systems (as opposed to those agents which are specific--the analogy being monogamous)

Avastin can in some circumstances cause a rebound effect (at least in mice). From what I hear sorafenib has been shown to sometimes have a reboudn effect in mice but not in people. It has been theorized (and some interesting slides at 2008 AACR ANNUAL MEETING SHOWED THIS OCCURING IN MICE) that the reason the blood vessels regrow SO rapidly is that the scaffolding on which they grown has not been destroyed so there is less work to regrow new blood vessels since they do not have to start from scratch.

Now that they have found the difference in behavior between MCSF and VEGF, you can bet your booties that they are going to be working on monoclonal antibodies (and perhaps TKIs against it) It is possible that some TKIs already in existence affect MCSF in their promiscuity. Until you know about something, you can't go looking for it!

[Rich66]

Imatinib suppresses breast cancer bone metastases by inhibiting osteoclasts
Will Boggs, MD


Last Updated: 2009-01-20 17:01:59 -0400 (Reuters Health)




NEW YORK (Reuters Health) - Imatinib mesylate suppresses bone metastases from breast cancer by blocking signals from the macrophage colony-stimulating factor (M-CSF) receptor c-Fms and thereby inhibiting osteoclasts, according to a report in the January 1st International Journal of Cancer.

"In addition to the direct anti-cancer effects, imatinib also has an inhibitory effect on osteoclasts, the key player in the development of bone metastases," Dr. Toru Hiraga told Reuters Health.

Dr. Hiraga and Dr. Hiraoki Nakamura from Matsumoto Dental University, Shiojiri, Nagano, Japan, investigated the effects of imatinib on bone metastases of breast cancer with a special focus on osteoclasts.

Imatinib attenuated the phosphorylation of c-Fms induced by M-CSF in mouse osteoclasts, the authors report, and dose dependently inhibited osteoclast-like cell formation induced by M-CSF and receptor activator of nuclear factor kappa-beta ligand (RANKL).

Imatinib also induced apoptosis in osteoclast precursors, but not at the low doses used to inhibit osteoclast differentiation.

Moreover, the researchers note, the lower concentrations of imatinib used to suppress osteoclast differentiation did not affect osteoblast differentiation.

In nude mice bearing bone metastases, imatinib significantly decreased the number and area of osteolytic lesions, as well as the metastatic tumor burden and osteoclast number in bone metastases, the investigators say, and these effects were reproduced by specific inhibition of c-Fms.

"The inhibitory effects of imatinib against osteoclastic bone resorption may provide a beneficial effect on cancer-induced bone loss, one of the frequent complications caused by hormonal therapy and chemotherapy," Dr. Hiraga concluded.

Int J Cancer 2009;124:215-222.

[gdpawel]

Rich

At the ASCO Breast Cancer Symposium in 2008, Dr. Weisenthal had shown that Tykerb enhanced the antivascular activity of Avastin. High dose, intermittent 'bolus' schedules of Tykerb to coincide with Avastin administration may be clinically advantageous, even in Her2-negative tumors. Avastin + Tykerb may be the first clinically-exploitable antivascular activity drug combination. It will take combination antivascular (anti-angiogenesis) therapy to make a big difference in cancer medicine.

http://www.asco.org/ASCOv2/Meetings/...stractID=40418

[Rich66]

Conclusions: 1. LAP has AV activity superior to that of sorafenib. 2. BEV + LAP may be the first clinically-exploitable AV drug combination. 3. Our functional profiling assay system may be used to individualize AV therapy. 4. High dose, intermittent 'bolus' schedules of LAP to coincide with BEV administration may be clinically advantageous, even in HER2-negative tumors.

I still don't know what is meant by "high dose intermittent bolus" of Tykerb. Usual dose, i.e. daily pill? Multiple pills but not every day?

I do remember seeing elsewhere that high dose Tykerb might be used before an infusion of chemo to prime the vasculature or the like.

[gdpawel]

Intermittent: occurring occasionally or at regular or irregular intervals; periodic.

Bolus: a single, relatively large dose of a drug that is administered for therapeutic purposes and taken orally.

I know with high-dose tamoxifen at concentrations of 2.5 micromolar or greater significantly inhibits the P-glycoprotein multidrug resistant membrane pump, as well as inhibiting protein kinase C.

[Rich66]

Well...I knew the intermittent part
How much oral TAM does it take to get to that level?

Ok..
Here's the study..and some other related studies:

A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies

Amy J. Chien1,6, Julie A. Illi6, Andrew H. Ko1,6, Wolfgang M. Korn1,6, Lawrence Fong1,6, Lee-may Chen2,6, Mohammed Kashani-Sabet3,6, Charles J. Ryan1,6, Jonathan E. Rosenberg1,6, Sarita Dubey1,6, Eric J. Small1,6, Thierry M. Jahan1,6, Nola M. Hylton4,6, Benjamin M. Yeh4,6, Yong Huang5, Kevin M. Koch7 and Mark M. Moasser1,6 Authors' Affiliations: Departments of 1 Medicine, 2 Obstetrics, Gynecology, and Reproductive Sciences, 3 Dermatology, 4 Radiology, 5 Biopharmaceutical Sciences, and 6 Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California and 7 Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina
Requests for reprints: Mark M. Moasser, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, Box 0875, San Francisco, CA 94143-0875. Phone: 415-476-0158; Fax; 415-353-7692; E-mail: mmoasser@medicine.ucsf.edu.
Purpose: Systemic chemotherapy fails to access much of the tumor burden in patients with advanced cancer, significantly limiting its efficacy. In preclinical studies, brief high doses of tyrosine kinase inhibitors (TKI) targeting the human epidermal growth factor receptor (HER) family can prime tumor vasculature for optimal chemotherapeutic delivery and efficacy. This study investigates the clinical relevance of this approach.
Experimental Design: A phase I clinical study of escalating doses of the HER TKI lapatinib given as a 2-day pulse before a weekly infusion of nab-paclitaxel (100 mg/m2) was conducted in patients with advanced solid tumors.
Results: Twenty-five patients were treated. Treatment was associated with grade 1 to 2 toxicities including diarrhea, nausea, rash, neutropenia, neuropathy, fatigue, alopecia, and anemia. The two dose-limiting toxicities were grade 3 vomiting and grade 4 neutropenia, and the maximum tolerated dose of lapatinib was defined as 5250 mg/day in divided doses. Lapatinib concentrations increased with increasing dose. Dynamic Contrast Enhanced Magnetic Resonance Imaging studies in a subset of patients confirmed a decrease in tumor vascular permeability immediately following a lapatinib pulse. Sixty-five percent of evaluable patients experienced a partial or stable response on this therapy, 72% of whom were previously taxane-refractory.
Conclusion: A 2-day pulse of high-dose lapatinib given before weekly nab-paclitaxel is a feasible and tolerable clinical regimen, suitable for testing this novel vascular-priming chemosensitization hypothesis developed in preclinical models. (Clin Cancer Res 2009;15(17):5569–75)



Anticancer Drugs. 2009 Nov;20(10):918-25.
Role of efflux pump activity in lapatinib/caelyx combination in breast cancer cell lines.

Vannini I, Zoli W, Fabbri F, Ulivi P, Tesei A, Carloni S, Brigliadori G, Amadori D.
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC), Italy.
The aim of this study was to investigate, at preclinical level, efflux pump modulation induced by lapatinib, a small-molecule dual inhibitor of the epidermal growth factor receptor (EGFR), in HER2-negative or HER2-positive breast cancer cell lines (SkBr3 and BRC230). We also evaluated the cytotoxic activity and modulation of biomolecular cellular pathways regulated by caelyx and lapatinib, used singly or in combination, at concentrations corresponding to peak plasma level in the two cell lines. Lapatinib was active in the HER2-overexpressing cell line, SkBr3, but not in BRC230 cell line, which does not express HER2. Conversely, caelyx exerted a cytotoxic effect on both the cell lines. Simultaneous exposure to lapatinib and caelyx in SkBr3 cell line produced an additive cytotoxic effect with dephosphorylation of HER2 and EGFR, an upregulation of p21, and an induction of apoptosis through dephosphorylation of BAD and caspase cleavage. In BRC230, simultaneous treatment induced a synergistic effect that was because of, at least in part, an upregulation of p21. Lapatinib also blocked efflux pumps, such as the breast cancer resistance protein I by increasing the length of time in which caelyx was present in tumor cell cytoplasm, which led to caspase cleavage, BAD dephosphorylation, and apoptosis. Our data indicate that lapatinib used in combination with caelyx is active in HER2-expressing cells, probably because of lapatinib-induced dephosphorylation of the HER2-EGFR pathway, and also in non-HER2-expressing cells, possibly because lapatinib blocks efflux pump activity, increasing the length of time of intracellular exposure to caelyx and thereby increasing its cytotoxic effect.

PMID: 19752719 [PubMed - indexed for MEDLINE]





Cancer Res. 2008 Oct 1;68(19):7905-14.
Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.

Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW.
State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Erratum in:

• Cancer Res. 2008 Dec 15;68(24):10387.

Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.

PMID: 18829547 [PubMed - indexed for MEDLINE]

[Rich66]

In the quest for here and now...
Maybe bisphosphonates like Fosomax or metronomic IV Zometa (Zoledronic acid) which can inhibit multiple actors like VEGF and Hif-1:

LINK

Although BPs may inhibit the resorption-stimulating activity by osteoblasts, it is evident from our studies on TRACP-positive mononuclear cells derived from bone marrow that BPs inhibit M-CSF and RANKL-induced fusion of osteoclast precursors in the absence of osteoblasts (Figures 2F and 2G).

Have to look into other antiangiogenic possibilities HERE for m-csf inhibition.

[Trish]

Thanks to all of you for the info in this thread. I was considering Avastin as I have been on Abraxane/Tykerb combo and while CT scan showed slight tumour shrinkage TMs have been skyrocketing. (CA 153 most recently 1659 while not a record for me it is well on the way and fast). I will discuss the Tykerb pulse technique prior to Abraxane with my onc.
Thanks again Trish

[Ellie F]

Hi knowledgeable people
Are there any natural sources of this compound??

Ellie