Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Stopping all red cars.
Paul, I like your analogy: "first find a way to direct all red cars to just one lane ... then stop all traffic in that lane."
This is exactly what is done with acute promyelocytic leukemia (APML). First the cells are directed to the "differentiate and proliferate" lane by all-trans retinoic acid, and then they are hit with the cytotoxic chemo agent, daunorubicin, thus stopping all traffic in that lane. It is one of the few huge successes in acute adult leukemias, with the ability to cure the majority of patients. This is made possible because of the particular genetic defect in APML.
Combinations are often rational, like combining a drug that blocks the ability to respond to oxidative stress (e.g. blocking the enzyme glutathione-S-transferase) with a drug that causes oxidative stress, like Cisplatin. That is why I would like to see something like anti-VEGF (Avastin), or a VEGFR2 receptor blocker (sunitinib, sorafenib) which causes hypoxia in tumors with something that blocks the protection against hypoxia, like Panzem/2ME2.
Best Regards,
C-Peptide
That is a question of immediate concern to physicians who are caring for the thousands of patients who are receiving bevacizumab (Avastin), sorafenib, or other VEGF-antagonizing drug as part of their cancer therapy. For example, taking a long-acting form of nitroglycerin to lower blood pressure may also restore some blood flow to a growing cancer, much as it restores blood flow to a damaged heart to treat angina, except that in the case of a cancer, you want to cause ischemic damage, not prevent it.
On the other hand, there is no evidence for this effect in patients. For all we know, the hypertension effect of VEGF antagonism applies to normal vessels only, and serves only to make the heart work harder to move the same amount of blood, which is generally bad. If the tumor vasculature is competing with other vessels in the region for flow, then something that constricts or dilates normal vessels will force more or less blood flow through the tumor. One view is that tumor vasculature is fixed to demand the maximum available flow, so that anything that lowers systemic resistance, like heavy exercise or blood pressure lowering medicine will competitively divert some flow away from the tumor.
The bottom line is that we don't know what is best, but we do know that cardiovascular health is improved with blood pressure control, so the prevailing wisdom is to treat it in more or less the usual way, usually with angiotensin converting enzyme inhibitors as the first-line.
Best Regards,
C-Peptide
Re: Multi-kinase inhibitors for autoimmune diabetes
There does seem to be a potential for a multi-kinase inhibitor, like ENMD-2076, to halt autoimmune diabetes in its early stage. The NOD mouse is not a perfect model of human type-1 diabetes, and the intervention would have to be very early in the disease, while enough viable insulin-producing cells still remained. (You can tell how many insulin producing cells remain by checking the c-peptide level.) Someone who has had type-1 diabetes for years will almost certainly not benefit.
In the future, if this type of multi-kinase inhibitor were combined with autologous stem cell derived beta cell transplantation, it might protect them while they become established. If the protection were long-term, this would represent a cure of type-1 diabetes. Type-2 diabetes, which is 10-20 times more prevalent, is a much more complex metabolic disorder, but less immediately dangerous, and largely reversible with diet, exercise, and weight loss.
There is a branch of cancer research devoted to the immunology of cancer, and how cancer cells protect themselves from immune attack. Devotees of the immunologic approach believe that our immune system regularly clears microscopic cancers long before there are any clinical signs. They are skeptical of therapies (like high-dose chemo) that damage the immune system, and are interested in therapies that remove the "cloak of immunotolerance" that some cancers acquire by recruiting regulatory T cells and secreting certain cytokines. If multi-kinase inhibitors also protect cancer cells from immune attack, just as they appear to protect NOD mouse beta cells, that would become part of their downside.
Best Regards,
C-Peptide
There are some concerns about bevacizumab (Avastin) in GBM that go beyond the well-known toxicities. There is a concern that Avastin, given over time, may select for stem-like, non-angiogenic, less-proliferative, but highly invasive GBM cells. Much is being learned from post-Avastin radiological and pathological analysis of these tumors in this regard. Preliminarily, there appear to be multifocal recurrences with increases in neural stem cell markers.
The key to clinical benefit from these narrowly targeted drugs, as always, is rational combination. For example, invasive, neural stem-like GBM cells appear to live off the PI3K-AKT pathway and its downstream players, like NF-kB and mTOR. There are several AKT inhibitors in development, as well as curcumin (against IKK/IkB/NF-kB) and rapamycin (Sirolimus) against the aptly-named mammalian target of rapamycin (mTOR). For those cells that are angiogenic, 2-methoxyestradiol (Panzem) is an obvious natural partner of Avastin against HIF.
I would not criticize the FDA for approving Avastin without clear single-agent benefit. As always, the question is not necessarily whether single-agent Avastin shrinks GBM tumors or lengthens median survival, though those are good things. The question is whether it can be an effective addition to a multi-component regimen. The sooner the FDA learns to get out of the way of innovation in this area, the sooner people will start living longer. The FDA is about to lose one of their champions in the Senate to this disease. They've failed him and us.
One way to assure explosive innovation would be to allow drugs to be marketed after phase 1 or 2 for all cancers that have a prognosis of less than one year, with the requirement that appropriate data be collected - a sort of generalized Abigail Alliance.
Reference:
1) Sakariassen et al, Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16466-71. Epub 2006 Oct 20.
http://www.pnas.org/content/103/44/16466.full.pdf
2) Fischer et al, High-grade glioma before and after treatment with radiation and Avastin: initial observations.Neuro Oncol. 2008 Oct;10(5):647.
http://neuro-oncology.dukejournals.org/cgi/content/full/10/5/700?view=long&pmid=18697955
3) Meng Law Brain Tumors: Post Treatment Imaging Los Angeles Radiological Society, Midwinter Radiology Conference - January 24-25, 2009
http://www.larad.org/meetings/MidWinter/2009/MWR09/Law%20Post%20Treatment%20Brain%20Tumors.pdf
4) Abigail Alliance: http://abigail-alliance.org/
Best Regards,
C-Peptide
2ME2 for preeclampsia is great news. I attended a symposium at Harvard where Dr. Folkman was one of the presenters almost 7 years ago. There I told an obstetrician who was also interested in Dr. Folkman's work that I thought 2-methoxyestradiol held enormous promise for preeclampsia, and that someone should look into it. Maybe someone did, but not in time to prevent my latest nephew from being born 2 months early with several weeks of great difficulty in the NICU, because of preeclampsia in my sister-in-law who also had a rough time. All is well now, but a drug that can prevent those problems will make History with a capital 'H'.
Ref: http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_E/threadview?m=tm&bn=6124&tid=31277&mid=31280&tof=-1&rt=2&frt=2&off=1
We are very, very, very circumspect about giving drugs to pregnant women, particularly in light of DES and of course thalidomide, and rightly so. The fact that 2-methoxyestradiol is an endogenous substance present at high levels in normal third trimester pregnancies should help it move into the clinic. Forget analogues. Were I an obstetrician, I would have submitted a trial protocol months ago.
Best Regards,
C-Peptide
The degree of benefit is not described in a way that is very useful. Response rates are notoriously bad predictors of overall benefit, particularly for the anti-angiogenic modality.
Best Regards,
C-Peptide
Looking back to the preliminary MKC-1 trial data from ASCO, ( http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=33394 ) is appears that as of the January 8, 2008 abstract deadline, 8 patients had been enrolled in the phase-1 dose-finding portion, which defined a dose of 75mg/m2 bid for the first 14 days of each 21 day cycle, and 11 patients had been enrolled in the phase-2 portion, of which one had stable disease for 8 months. Hopefully accrual picked up once the dose was defined and very preliminary positive signs were observed. In a population where the median time to progression is 12-15 weeks, it does not take very long to demonstrate something significantly better than that.
The most pessimistic scenario consistent with the data is that accrual was slow, only 31 of the planned 60 patients have been accrued so far, and all but one of them progressed or died in a few weeks, but not so fast that the data safety monitors halted the trial early, thus meeting the primary efficacy endpoint in a very lousy way.
The most optimistic scenario consistent with the data is that accrual was fast, about 2 per week, and all 60 patients were accrued by around July 1st, with the median patient accrued around April 1st. If 30 of them were cured oughtright, and it took until last week for the remaining 30 to progress, then that would be a median progression free survival of about 30 weeks, which would be a moonshot result.
The truth is probably somewhere in between.
Best Regards,
C-Peptide
spin
Having seen how the press release sausage is made up close, I chose my words carefully. I very much doubt that those were Dr. Sidor's words, but rather the words of a PR person which were intended to convey encouragement that the next phase in the development of MKC-1 can proceed. The fact that this next phase depends of the harsh reality of median progression free survival (or progression or death in half the patients, which is the same thing) is not something about which I would expect a PR person to think, or to look beyond the euphemistic clinical trial language.
Like rubberchicken said, "efficacy endpoint" sure sounds better than a sharp stick to the eye, even though most patients would rather have the stick's endpoint in their eye than being a contributor to the efficacy endpoint statistic.
Best Regards,
C-Peptide
Primary efficacy endpoint...
I would read these words with caution. According to the trial description at clinicaltrials.gov ( http://www.clinicaltrials.gov/ct/show/NCT00408226 ), the trial will "... determine the antitumor activity, based on the objective response rate and median Progression Free Survival ("PFS")...".
In that case, the endpoint is met when half of the patients progress or die. Needless to say, the sooner this endpoint is met, the worse it is for efficacy. I find that the quote Dr. Sidor allowed to be attributed to her makes for uncomfortable reading: "We are pleased to have met the primary efficacy endpoint in the first stage of this study." Which loosely translates to "We are pleased that at least half of the patients in the trial have either had objective progression of their disease, or have died." If MKC-1 were the ideal cancer drug, the primary endpoint would not be met for many years.
The study began recruiting patients in the final months of 2006, and planned for 60 patients. Median progression-freee survival for advanced, pretreated NSCLC, based on recent ASCO trial reports ( http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts ), is somewhere in the neighborhood of 10-15 weeks. Median overall survival is somewhere in the neighborhood of 35-40 weeks. If it took a year to accrue the patients (at a rate of 1-2 per week), then the "median" patient was recruited in mid-2007. For a drug with no effect, you might expect median progression-free survival to be reached late in 2007, and median overall survival to be reached in mid-2008. It might take longer than that if patient accrual were slow, or if the drug is effective. Until the details are released or deduced, we will not know.
Best Regards,
C-Peptide
Re: OT question
Usual disclaimer applies here about not giving specific medical advice, just general information.
I think it helps to become involved with an on-line support group, but an investment stock board is not your first choice. You can try http://www.acor.org . Many hospitals help organize and host regular meetings of patient groups, for face-to-face peer support.
Eloxatin (oxiplatin) is generally given as part of a combination like "FOLFOX" which is standard for colorectal cancer these days, and significantly prolongs survival in appropriate patients. It is usually tolerated fairly well, especially compared with its predecessor, cisplatin, with fewer acute side effects and less toxicity. I have seen patients get neuropathic symptoms, which can be very uncomfortable, but almost always resolve by the next day. I have seen patients continue working full time while on this regimen, but everyone is different. If she has "heard horrible things" they may be about cisplatin and not oxiplatin. It seems like people who got cisplatin never forget the violent nausea. Sometimes people use language loosely. The majority do get nausea, but that us usually managed well after some trial and error with the anti-nausea meds during the first round.
As far as specific medicines to mitigate side-effects, there are standard anti-nausea medicines which all patients get. I am not aware of any medicines that successfully address the transient neurologic side-effects which not all people get anyway.
You and your mom might want to have a frank discussion with her oncologist about this. You might also discuss clinical trials in your area, which are an under-utilized patient resource. There are many "targeted" therapies entering trials that have significant promise, especially in combinations of two, three, or four targeted therapies.
For good lay-level information on cancer I can recommend the NCI site:
http://www.cancer.gov/cancertopics/types/colon-and-rectal
http://www.cancer.gov/cancertopics/cancer-advances-in-focus
For health professional level information, http://www.asco.org is a good initial choice.
Best wishes to you and your mom as you meet this difficult challenge.
Best Regards,
C-Peptide
Blocking glycolysis is the least of Panzem's effects
It is unfortunate that this quote, "Blocking HIF1 activity interferes with the tumor's ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth," was chosen for the article. The truth is much more complicated. 2-methoxyestradiol partly reverses a major "switch" in how cells become dangerous. Energy production is the least of a cancer cell's problems. Reducing the energy available to them will not help patients. After all, cancer cells have already reduced their available energy by 93%.
It has been known since the 1920s that cancer cells all but turn off the method of energy production called oxidative phosphorylation (OxPhos) which occurs in the mitochondria, in favor of glycolysis which occurs in the cytosol. In the process the energy efficiency of the cell is reduced to about 7% of normal, because OxPhos makes about 15x as much energy per molecule of glucose. Mitochondrial enzymes are also key players in the process of programmed cell death, called "apoptosis," which is triggered when a cell recognized that it is "broken." This is part of a larger de-differentiation of the cell to a more primitive, proliferative, invasive phenotype. If 2-ME2 can cause the cell to switch back to something resembling the cell it came from, by blocking the oxygen-independent expression of HIF-1, it is likely that programmed cell death will be the result, and failing that, a far less malignant cell.
Upstream of HIF-1 is the PI3K/AKT pathway, which is also blocked by 2-methoxyestradiol, and which among other things increases HIF-1 expression, lengthens telomeres, and promotes angiogenesis. It is an upregulated pathway in practically all cancers. It is a very important target for anti-cancer therapy.
Refs:
http://www.ncbi.nlm.nih.gov/pubmed/17680560
http://www.imgenex.com/emarketing/Akt_Signaling1_fullsize.jpg
Best Regards,
C-Peptide
P.S. Despite the development of analogues and the pharmacokinetic fiasco that was EntreMed's management of oral Panzem, let's not lose sight of the fact that 2-ME2 is what our own bodies have used for countless generations to regulate angiogenesis and cell proliferation, at least in certain circumstances. This confers an enormous presumption of safety. But, as a practical matter, ever since the discovery of insulin the delivery of concentrated physiologic molecules in a therapeutic way has been problematic. Analogues are here to stay, but what we lose in the pursuit of convenient delivery is the confidence that untoward effects are not likely to be lurking around the corner.
Re:Mayo/2ME2 + paclitaxel
I think you make the point well. Even when single-agent 2ME2 shows significant activity, you will not want to use it that way. You will pair it with an agent that has proven, but limited efficacy. If there is a role for single-agent 2ME2 it will likely be in that future that MJF envisoned, when a blood test can detect ultra-early disease, prior to any detectable tumor, and it is the marker (not the tumor) that is followed and treated.
Best Regards,
C-Peptide
Panzem combos - Got a HIF1 blocker?
It baffles me why you would say, "The most painful part of Burns' presentation, to me, was the acknowledgment that Panzem will no be pursued as a single agent oncology drug". What is wrong with a drug that is likely to potentiate just about every oncology regimen out there without significant new toxicity? Even MJF, who saw the promised land from the mountain of his intellect, but, alas, did not live to reach it, described the main use of anti-angiogenics as part of a combination approach. Single-agent Panzem has always been an isolated hope, but never a general expectation.
Recurrent, refractory gliomas, metastatic carcinoid, and breast cancer metastatic to bone are considered NOT curable, and yet Panzem combos may ultimately prove to have cured one of each of these already. Panzem + Temodar, Panzem + Docetaxel, Panzem + Avastin, and wait until you see the data for Panzem + Sunitinib and Panzem + Sorafanib. These are combos where Panzem specifically plugs the holes in the other therapies that allow tumors to escape.
Sometimes I try in these boards to whisper in the ears of the pharmaceutical and cancer research communities, never expecting that what I suggest will actually be adopted, or if it is, only coincidentally so. I am very pleased that what I posted 11 months ago in IHub/ENMD #5230, appears to be actually happening: "Now there are a multitude of tyrosine kinase inhibitors targeted to VEGFR, PDFGR, EGFR, etc, both approved and in trials, that run the risk of being partially counteracted by the HIF-1 response. If the makers of these drugs are smart, they should be aggressively pursuing the combination of their drugs with anti-HIF drugs like Panzem in order to have the best possible clinical trial results, the fastest possible approvals, and the widest possible indications."
The makers of this new generation of targeted drugs know that the angiogenic and survival response mediated by HIF1 is their Achilles heel. They are not stupid, so they are addressing this weakness. They are seeking a potentiating agent like Panzem to either push efficacy further, or as a way to reduce the dose-related side-effects into a tolerable range without losing the benefit.
Best Regards,
C-Peptide
Re: Dr. Judah Folkman.
He was my role model for what a physician-scientist should be.
The loss of his leadership and creative energies is devastating.
But he has inspired many others, including me, to carry the dream forward.
RE: Anti-TNF for Alzheimer's
Goodbugs, you are asking if there is any chance that the small-molecule, anti-angiogenic, tubulin-binding, and TNF-downregulating molecule ENMD-1420 (formerly Celgene's CC-5079) could be used to help Alzheimers dementia, perhaps in a way similar to the dramatic findings reported in the Journal of Immunology by Tobinick & Gross [1], and summarized in the accompanying commentary by Griffin [2], when etanercept, an anti-TNF antibody, was administered into spinal fluid.
If we assume that ENMD-1420 has free access across the blood-brain barrier, it is still unlikely that anything like the dramatic results reported for etanercept (which have yet to be independently verified) will be produced. Downregulating the production of TNF is very different from directly scavenging pre-existing TNF. Also, there is a possibility that some cross-immunization by the anti-TNF antibody against the amyloid beta plaques of Alzheimers is responsible for the apparent durability of the treatment.
Also, another potent inhibitor of TNF is thalidomide, which does have free access to the central nervous system (somnolence is a side-effect). It has been used widely enough that if it produced significant benefit against Alzheimers, it should have been noticed by now. Furthermore, although anti-inflammatory and anti-TNF therapy of the brain is a promising line of research, a case report by Morgan et al from a 2003 reports the reversible induction of dementia by thalidomide in a man receiving it for multiple myeloma.
The etanercept results are startling and impressive. Furthermore, it is an approved drug that can be used today. If someone close to me were dealing with Alzheimers dementia, I would aggressively explore the possibility of becoming involved in a trial of spinally administered etanercept.
If I were looking for a small-molecule that might give an edge when added to standard Alzheimers therapy, the best clinical evidence points to ibuprofen, and the epidemiologic evidence supports curcumin, an anti-inflammatory phytopolyphenol that directly binds amyloid beta plaques. Both of these are subjects of active research. Although neither of them have proven efficacy, the downside is minimal.
References (freely accessible full text):
1. Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008 Jan 9;5(1):2 [Epub ahead of print]
http://www.jneuroinflammation.com/content/pdf/1742-2094-5-2.pdf
2. Griffin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5(1):3 [Epub ahead of print]
http://www.jneuroinflammation.com/content/pdf/1742-2094-5-3.pdf
3. Morgan AE, Smith WK, Levenson JL. Reversible dementia due to thalidomide therapy for multiple myeloma. N Engl J Med. 2003 May 1;348(18):1821-2.
http://www.ncbi.nlm.nih.gov/pubmed/12724497
You are absolutely right, George. There should be some tolerance of tumor growth in the early phase of antiangiogenic therapy. If a cytotoxic drug at the maximum tolerated dose (MTD) is not shrinking a tumor after one month, it is unethical to continue it. However, if a drug is more angiostatic than tumoricidal, a period of growth should be expected, and tolerated, particularly if the drug is not particularly toxic and the overall clinical picture is not worsening.
Trial protocols are written so that useful data can be obtained, and the generous gift of patient participation is not wasted. What the rules are is less scientifically important than the uniform adherence to them, so that nothing clouds the statistics. It is hard for some people who have been writing trial protocols one way their whole professional lives to change, even if the new drug warrants it. The protocol is more likely to be assembled from the boilerplate of prior trials and modified slightly than written from scratch by the person with the deepest knowledge of the drug and the likely responses to it. Change is hard.
Best Regards,
C-Peptide
I can't speak for George, but I'll jump in with my take.
First, on the question of isolating & purifying the "active" compound from a dietary source, rather than using the natural food source, there are strong arguments on both sides. It is important to remember that many of our big pharmaceutical drugs got their start from purifying the constituents of plants or molds. I prefer to take my caffeine from roasted and freshly ground beans, but I'll take my penicillin in purified form.
One of the arguments for why the overwhelming epidemiological evidence that diets high in vitamins C, E, and beta carotene confer health benefits has not been reproduced by studies of supplements is that dietary sources contain other substances that are the true source of the benefit, or that the balance in the amounts and way they are absorbed from food is as important as the substances themselves.
Adding more support to the "Whole Food" hypothesis is the latest curcumin formulation from the Life Extension Foundation (LEF). Curcumin is famous for its exploding literature as a potential anti-cancer, anti-inflammatory dietary supplement, but infamous for its poor bioavailability. Previously, the LEF had formulated their curcumin with piperine (from black pepper) to inhibit the enzymatic modification and clearance of curcumin, with much greater bioavaliability than the pure supplement. Last month, they published their results with a new formulation that dramatically increased bioavailability further by making the supplement less pure, leaving in many of the other constituents of turmeric root. (Ref: http://lefcms.lef.org/magazine/mag2007/oct2007_report_curcumin_01.htm )
So, despite the fact that the standard model of, find it, purify it, maybe make a patentable analogue of it, and sell it, has been very successful for hundreds of medicines or supplements, it pays to approach the use of medicines or "nutraceuticals" derived from foods and traditional cultural medicines with considerable humility.
The richest source of resveratrol is reported to be the rhizomes of japanese knotweed. It grows wild all around where I live, and is considered an invasive, undesirable escapee from domestic landscaping and gardens, similar to purple loostrife. I am seriously considering digging some up, cultivating it in the back meadow, and making extracts of it as a hobby. Sirtris Pharmaceuticals will have to compete with my ability to make my own.
Both EntreMed and Sirtris are relying on the fact that despite the non-patentability of their lead molecules, they can still patent their formulations and their uses. That is some protection, but it is considerably less than that enjoyed by a patented molecule.
Look at the evidence base for fish oil. If Pfizer owned the patent on it, studies like the GISSI-Prevenzione trial would have been done decades ago. There would have been lavish educational lecture dinners touting the results. Fish oil would be prescribed more often than statins today if it weren't a natural, non-patentable product.
Now we have Lovaza (previously Omacor), which is a super-concentrated DHA/EPA supplement, that is patented, has an FDA-approved indication, and costs 6 times as much ($1.30/gm) for the same amount of active ingredient as OTC fish oil ($0.21/gm). The prescription dose is 4gm/day. The racket is that people with prescription drug coverage can buy it for their co-pay, which might be $5 less than an equivalent purchase of OTC fish oil, thus engineering a wealth transfer from the taxpayer to Reliant Pharmaceuticals of $130/month per subscription instead of $25/month to a reputable fish oil seller for the same thing. (Or eating 7oz of salmon per day, which would cost $120/month at my local, upscale supermarket, selling wild salmon at $9/lb.) Again, this assumes a dose of 4gm/day for the FDA indication of hypertriglyceridemia with TG>500, but there is strong evidence of cardiovascular benefit at 1gm/day for the rest of us. I spend about $6/month for 1.2gm/day.
Price references:
https://online.epocrates.com/u/10a4013/Lovaza
http://www.lef.org/newshop/items/item00625.html
Best Regards,
C-Peptide
Sorry, typo, should be 0.27-0.66g/mL. -CP
As you probably know, I've complained in these forums (fora?) for over 3 years about how EntreMed failed to incorporate the lessons of oral contraceptive bioavailability and pharmacology into their 2ME2 development plans, for which the trial patients and the company have payed dearly.
I think subcutaneous delivery, rectal or vaginal suppository delivery, and transdermal delivery are all deserving of exploration and are likely to be more effective than any oral regimen that does not also include specific inhibitors of glucuronidation, including the current Panzem NCD trials.
The challenge with subcutaneous delivery is the volume required to deliver multi-gram doses every day, especially given the poor solubility of 2ME2. A typical patient might require 2-5gm/day of 2ME2. The largest reasonable single subcutaneous injection is about 2.5ml, so for TID dosing, that would require a formulation that had 0.27-0.66mg/mL, which I think is about 3-6x the current maximum concentration.
I think 2ME2 is highly amenable to a norplant-type implantable depot. This is metastatic cancer we're fighting here, so a minor surgical procedure to implant basically a brick of the stuff, or to implant a refillable pump, might not be too much to ask.
For rheumatoid arthritis, lower and much more easily given doses are probably more than sufficient.
Best Regards,
C-Peptide
2ME2 has been studied since before EntreMed, as a known metabolite of estrogen for at least 50 years. They don't own a patent on the molecule, which is in the public domain. They own patents on a method for producing and purifying it, and on certain uses of it. Calbiochem can sell it and anyone can do research with it. Obviously it is in EntreMed's interest to encourage as much outside research on it as possible. Researchers run the risk of estrogenic impurities from non-EntreMed 2ME2, but that's not an issue for many purposes.
Best Regards,
C-Peptide
Mayo study is not direct 2ME2 injection into tumors.
I just finished reading the paper. There seems to be the misconception that a daily dose of 50 mg/kg of 2ME2 was injected into mouse femurs. (Here I ask you to compute your own dose in your head and do the thought experiment of injecting it into your femur EVERY DAY. For me that's 5 grams of 2ME2 in what I estimate to be 10-20ml of 95% ethanol. Mega-Ouch!) The tumor cells were injected into the bones directly, but the daily 2ME2 dose was injected subcutaneously, like insulin, although I have to believe they diluted the 95% ethanol vehicle. The maximum volume for intermittent human subcutaneous injection that can be delivered comfortably is about 2.5ml, so at TID dosing, getting me 5gm/day of Panzem in 7.5ml of vehicle is close to the limit.
Also, the 2ME2 came from Calbiochem ( http://www.emdbiosciences.com/product/d/454180 ), not EntreMed.
In any case it is a great study that supports the use of 2ME2 in all the ways we have discussed.
Therapies that involve direct tumor injection of drugs, genes, radiation, electricity, etc., are NOT the future of oncology, in my opinion. You will never inject every cell, and you are back to the old "target the tumor" game, which MJF compares to pre-antibiotic surgical treatment of infection. "Where's the pus? Drain the pus."
"Where's the tumor? Inject the tumor." does not represent progress in my mind, regardless of the modality. Progress will be in blocking the support the parasitic tumor cells receive from the normal stromal cells, in the form of blood vessels, growth factors, and adhesion signals.
Best Regards,
C-Peptide.
This is a smart use of the royalty stream.
It is non-diluting. It essentially accelerates these revenues from the future into the present, with some cost, to fund something that is likely to dramatically increase market valuation. Isn't that better than diluting while undervalued?
Also, I agree with docaaron that it represents a vote of confidence by a group of financiers who have strictly bottom-line concerns.
This does make EntreMed a more speculative investment than it was (if that's possible). The stock gets part of its value from the more or less steady Thalomid stream, of which the stockholders now own less, in order to own more of the future success of Panzem. We need to stay alive while waiting for the Panzem+Avastin for carcinoid and maybe the Panzem for ovarian phase-II trial results. A bridge that gets us there without diluting is a good one.
Best Regards,
C-Peptide
More evidence for 2ME2's cardiovascular beneifts.
Great report, George. Notice the dose!
The "high" dose in a rat was 100micrograms/day, or about 0.33mg/kg.
That scales to only about 25mg/day in a 175lb person to completely
reverse the effects of losing endogenous estrogen on monocyte adhesion.
It is not hard to envision Panzem as:
- the new HRT for post menopausal women
- a new "aspirin" for cardiovascular protection in general
- a revolutionary disease-modifying anti-rheumatic arthritis medicine
- a potentiator of practically every modality of treating practically every cancer
These are huge indications, with the potential to prevent more mortality and morbidity than any drug since penicillin.
Best Regards,
C-Peptide
Re:Vit. C against HIF-1a
I was arguing for vitamin C as a potential agent against HIF-1alpha via increased proline hydroxylase activity and decreased ROS at least as far back as 2002 [1]. You may recall that the first mechanism of action proposed for 2ME2, in 2000 by Huang et al [2] at MDA, was as an inhibitor of superoxide dismutase, resulting in increased ROS and cell death. A controversy erupted in the literature when Kachadourian et al asserted that no such inhibition took place, but that ROS were elevated by another mechanism [3]. When the 2ME2/HIF-1alpha story [4,5] took off in 2003-4, SOD and its attendant controversies receded into the background.
Vitamin C as a suppressor of HIF-1alpha was validated in 2003 by Knowles et al [6] in the lab of the same Peter Ratcliffe who has done so much work on HIF-1alpha as a mediator of angiogenesis and other tumor survival mechanisms. The full clinical significance of this has yet to be elucidated.
Which is all a long-winded way of saying that the argument for synergy between Panzem and high-dose vitamin C is a good one that has deserved investigation for some time now, particularly when combined with radiation therapy (e.g. post-lumpectomy), where high-dose vitamins C and E have the potential to protect healthy tissues from damage while potentiating the anti-cancer effects of radiation [7,8,9,10,11].
Best Regards,
C-Peptide
Refs:
1. http://messages.finance.yahoo.com/Business_%26_Finance/Investments/Stocks_%28A_to_Z%29/Stocks_E/thre...
2 Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature. 2000 Sep 21;407(6802):390-5.
http://www.nature.com/nature/journal/v407/n6802/abs/407390a0.html
3. Kachadourian R, Liochev SI, Cabelli DE, Patel MN, Fridovich I, Day BJ. 2-methoxyestradiol does not inhibit superoxide dismutase. Arch Biochem Biophys. 2001 Aug 15;392(2):349-53.
http://dx.doi.org/10.1006/abbi.2001.2455
4. Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell. 2003 Apr;3(4):363-75.
http://dx.doi.org/10.1016/S1535-6108(03)00077-1
5. Ricker JL, Chen Z, Yang XP, Pribluda VS, Swartz GM, Van Waes C. 2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha, tumor growth, and angiogenesis and augments paclitaxel efficacy in head and neck squamous cell carcinoma. Clin Cancer Res. 2004 Dec 15;10(24):8665-73.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15623651
6. Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ. Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res. 2003 Apr 15;63(8):1764-8.
http://cancerres.aacrjournals.org/cgi/content/full/63/8/1764
7. Prasad KN. Rationale for Using High-Dose Multiple Dietary Antioxidans as an Adjunct to Radiation Therapy and Chemotherapy. J. Nutr. (2004) 134:3182S-3183S.
http://jn.nutrition.org/cgi/content/full/134/11/3182S
8. Borek C. Antioxidants and Radiation Therapy. J. Nutr. (2004) 134: 3207S-3209S.
http://ict.sagepub.com/cgi/content/abstract/3/4/333
9. Seifried H, et al. Free Radicals: The Pros and Cons of Antioxidants, Executive Summary Report. J. Nutr. (2004) 134: 3143S-3163S.
http://jn.nutrition.org/cgi/content/full/134/11/3143S
10. Kumar B, et al. D-Alpha-Tocopheryl Succinate (Vitamin E) Enhances Radiation-Induced Chromosomal Damage Levels in Human Cancer Cells, but Reduces it in Normal Cells. J. Am. Acad. Nutr. (2002) 21(4):339-343.
http://www.jacn.org/cgi/content/full/21/4/339
11. Ladas EJ, et al. Antioxidants and Cancer Therapy: A Systematic Review. J. Clin. Onc. (2004) 22(3):517-528.
http://jco.ascopubs.org/cgi/content/full/22/3/517
Thx George. The PPAR-gamma story commands attention.
I am particularly impressed with the central role described for PPAR-gamma in the endothelial cells of tumors. When you add that to the recent safety concerns for the thiazolidinediones, or "glitazones", like Avandia, and the animal studies showing CARCINOGENESIS [1] with PPAR-gamma agonists, I would now think long and hard before prescribing a PPAR-gamma agonist for a diabetic [2].
If I were a reviewer of the paper, I would insist that the authors double-check, and clearly state, that the chronic pancreatitis patients, and the pancreatic cancer patients from whom surgical specimens were obtained, and who may be diabetic from pancreatic dysfunction or resection, were not taking a "glitazone", which would obviously be expected to produce the immunohistochemical results shown.
The reference [1] below states: "Mechanistic data to explain MOA for tumor formation [from PPAR agonists] is not available." It appears that mechanistic data is now available.
References:
1. El-Hage, J. Preclinical and Clinical Safety Assessments for PPAR-gamma Agonists http://www.fda.gov/cder/present/DIA2004/Elhage.ppt
2. Wikipedia: Rosiglitazone http://en.wikipedia.org/wiki/Avandia
Best Regards,
C. Peptide
Re: topical panzem
As long-timers know, I've been an advocate of topical 2ME2 for years as a way to get around the first-pass metabolism problem. Another company, PR Pharmaceuticals is developing 2ME2 in a monthly injectible depot formulation for the indication of pulmonary arterial hypertension. I've mentioned earlier how I think the IP aspects of that will play out.
There are problems with topical 2ME2 for treating systemic disease, based on the amount that would be needed. Although the idea is the same as estriadiol in a contraceptive patch, the dose is orders of magnitude larger.
For inflammatory/angiogenic skin diseases, like psoriasis, eczema, maybe discoid lupus, and probably even cutaneous T-cell lymphoma, where local concentrations can be much higher than the systemic, a panzem cream or ointment has a good chance of being more effective and more safe than anything out there.
I've also always advocated the idea of suppository 2ME2 delivery as an ...er... end-run around the first pass metabolism, but Americans tend to be pathologically squeamish about that. Europeans don't seem to mind. It is the ideal anti-emetic route. Swallow a pill for nausea and vomiting? How dumb is that?
Best Regards,
C-Peptide
Cecee, I'm very glad that Panzem seems to be helping your brother, even if he is the exception in this early phase trial. It is a very impressive sequence of MRI images on the poster. It is exceptions like him that get doctors excited about practicing medicine, not only because someone has been helped, but because his experience with Panzem may shed some light on the question of who is more likely to be helped by it, whether it be PTEN mutations, or some dietary supplement he takes, or something inherently different about the way his body metabolizes 2ME2. This is what phase II trials are for, and I thank Gary and all the other trial participants, past, present, and future, who turn their misfortune of a bad cancer diagnosis into a way to improve therapy for everyone with the disease.
The big problem with Panzem has always been the rapidity with which it is removed from circulation by metabolizing enzymes. Anti-seizure drugs are infamous for raising the levels of these enzymes. Today's poster shows how they cut in half the level of circulating Panzem. Mice don't have nearly as many of these enzymes as humans because they are the descendants of herbivores who don't need to break down the mammalian hormones in their food to keep from having miscarriages and fertility problems. I think that is the main reason the mouse models haven't been reproduced in people.
Best Regards,
C-Peptide
Can 2ME2 improve acute stroke outcomes?
I met a woman who arrived in the hospital yesterday with a devastating stroke to her middle cerebral artery (MCA). It left her unable to speak, with half of her face and body paralyzed. She was among the 3% of stroke victims who arrive in time to receive tPA, less than 3 hours from the onset of symptoms. It worked. She had no bleeding complications. Today she's fine. A miracle of modern medicine snatched her from the jaws of a permanent, devastating neurological injury.
The holy grail of acute stroke therapy has always been to extend the 3 hour window in which clot-busting drugs can be used, so they can reach more than 3% of stroke victims. The problem is that beyond that, too many neurons die, and too many of the remaining ones can not withstand the reperfusion injury, which causes much more harm than the direct ischemic injury. An agent that protects neurons from post-reperfusion inflammatory damage could potentially add hours to the usefulness of tPA and rescue thousands of additional stroke patients every year from the most devastating consequence of their illness.
Chen et al in study published in the Journal of Neurochemistry on 26-May-2007 via early electronic release, demonstrate just such an agent in a rat model of stroke, using 2ME2 combined with tricyclodecan-9-yl-xanthogenate (D609). They conclude, "2ME2 and D609 reduce the infarct volume ... and blood–brain barrier extravasation, decrease the mortality and improve the neurological deficits. In conclusion, 2ME2 and D609 are powerful agents to protect brain from cerebral ischemic injury by inhibiting HIF-1? expression, attenuating the superfluous expression of VEGF to avoid blood–brain barrier disruption and suppressing neuronal apoptosis via BNIP3 pathway."
You can improve your chance of surviving a heart attack by chewing an aspirin. Perhaps the day when you can improve your chance of recovering from a stroke by drinking some Panzem NCD is not far away.
Best Regards,
C-Peptide
JNM Abstract on 2ME2 biodistribution in mice.
It is freely available at:
http://jnumedmtg.snmjournals.org/cgi/content/meeting_abstract/48/MeetingAbstracts_2/309P-b
It is the abstract form of a conference poster.
Best Regards,
C-Peptide
Increasing 2ME2 bioavailability
There is a long list of UGT1A1 inhibitors that are safer than indomethacin, which as a potent NSAID, can cause gastrointestinal bleeding, and may also have increased cardiovascular risks associated with it, via the "Vioxx effect." Ref: JAMA. 2006;296:1633-1644 http://jama.ama-assn.org/cgi/content/full/296/13/1633 .
You have heard of many of these inhibitors, which in addition to being safer, are more potent. Piperine is 5x more potent than indomethacin.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=8347144
Silybin, from milk thistle, is 35x more potent than indomethacin.
http://dmd.aspetjournals.org/cgi/content/full/32/6/587
Many other compounds compete with 2ME2 for glucuronidation, including EGCG (from green tea), curcumin (from turmeric), quercetin (from many foods), and capsaicin (from peppers). http://www.jbc.org/cgi/content/full/279/2/1429
http://www.jbc.org/cgi/content-nw/full/279/2/1429/TBL4
One can not help but notice that most of these compounds are under active study for suspected anti-cancer and often anti-angiogenic properties of their own.
However, drugs and dietary substances that are substrates for the P450 and UGT enzymes are also sometimes inducers of them, most famously phenobarbital. It is not always clear where the balance lies. http://www.springerlink.com/content/u7m231387m482w32/
The first dose of substance X may make 2ME2 dramatically more bioavailable, but
the model of controlling cancer as a chronic disease requires chronic administration over the long term. If the body responds to substance X by making 1000x more 2ME2-degrading enzyme a month later, that's not good.
Chronic administration over the long term also requires that the substance have little or no toxicity. The best (though by no means only) place to look for low-toxicity substances is in foods that have been part of cultural diets and cultural medicines for centuries if not millennia.
Best Regards,
C-Peptide
Patient stories.
Of course we are heartened to learn of positive patient stories, especially for a disease like GBM. I would like to remind all concerned that the purpose of patient forums is to allow patients and those that love them to exchange information that can be supportive and helpful in the battle against their illness. Speaking for myself, I would hesitate to paste content from, or links to, those forums in places like the Yahoo stock message boards, or this board for that matter.
I have read every message in this forum, and met many of you in person, so I know that the human side of this struggle has always taken priority over the prospect of financial gain by investing in a successful venture. Nevertheless, the perception upon seeing her words in a stock message board of a sister who is helping her brother fight for his life, by seeking information and fellowship from others in a similar struggle, might be quite different, and might inhibit the process the forums were intended to facilitate.
I am not accusing anyone of anything. Most patient support forums are wide open, without passwords or memberships, in order to be as available as possible. Participants know that the internet, (to borrow from M. Ramirez), is what it is. But we can still try to push it from what it is towards what it ought to be.
Oh, and one more thing. Go Panzem!
Best Regards,
C-Peptide
Haod. You overestimate me.
Re: "You should just about be through with your fellowship now- How did it go - or are you going to take 3 yrs and do Heme too?"
While I would have liked to go straight from medical school to oncology fellowship, there is this small matter of a three-year internal medicine residency, of which I have completed nearly two. Having decided to try to repair some of the damage to my family life with a year of lighter duty, I will not be starting my oncology fellowship until July 2009. Nevertheless, I have had the opportunity to do some laboratory research on an emerging, natural anti-cancer compound, and I've steered some patients towards appropriate clinical trials of anti-angiongenic therapies.
Best Regards,
C-Peptide
Heck, George, I'd try Panzem with chicken soup.
However, with respect to your citation of the article that shows mithramycin modulates the activity HSD17B2 through the SP1 transcription factor, which presumably would allow Panzem to remain active and unmetabolized longer, it is worth some study, but SP1 is a transcription factor that affects many genes, both pro-tumor and anti-tumor. I would rather see a combination with a direct inhibitor of HSD17B2, similar to the combination of levodopa+carbidopa in Parkinson's Disease or curcumin+piperine. In fact, I suspect panzem+piperine might be quite good at increasing the bioavailability of Panzem by inhibiting glucuronidation but the gut. (Besides, most cancer patients don't have an endometrium, at least not an active one.)
Best Regards,
C-Peptide
Role of anti-HIF-1 medicines like Panzem
These recent posts on the role of HIF-1 in the promotion of tumors and their metastases, and the efficacy of substances that inhibit it, highlight what I've always thought were the shortcomings of the anti-VEGF and anti-proteasome treatments. In the case of anti-VEGF, the reduced blood supply provokes a HIF response that can lead to a more aggressive phenotype that is harder to suppress. In the case of the anti-proteasome approach (like Velcade), you are increasing HIF-1 by blocking the enzyme that removes HIF-1a in a high-oxygen environment. Blocking the proteasome is a very blunt instrument, and like blocking metalloproteases, it blocks both pro-tumor and anti-tumor processes. The net balance may be favorable or unfavorable in different microenvironments. In the case of metalloproteases we learned the hard way that the balance was too often unfavorable.
In both cases, there is an opportunity for anti-HIF-1 therapies, like 2-ME2 and its synthetic and natural cousins, to synergize with and potentiate other treatments. Given their low toxicity, there is practically no cancer treatment that is not likely to benefit from the addition of one of these. You can be sure that if I was being treated for almonst any malignancy, I would be washing down my curcumin and Celebrex with pomegranate juice, and enjoying Pinot Noir in moderation, while waiting for Panzem's approval. (That's not advice, just what I would do.)
Now there are a multitude of tyrosine kinase inhibitors targeted to VEGFR, PDFGR, EGFR, etc, both approved and in trials, that run the risk of being partially counteracted by the HIF-1 response. If the makers of these drugs are smart, they should be aggressively pursuing the combination of their drugs with anti-HIF drugs like Panzem in order to have the best possible clinical trial results, the fastest possible approvals, and the widest possible indications.
Best Regards,
C-Peptide
Re: Endothelial permeability and 2ME
The cited article demonstrates that a transient, reversible decrease in the resistance to electrical current becomes measurable above 0.1uM, significant above 2uM, and decreased resistance to the actual movement of small molecules becomes significant above 20uM. This is orders of magnitude higher than the goal trough concentration of around 0.04uM for sustained anti-cancer activity. The authors acknowledge this:
"In this study, we demonstrate that 2ME is able to elicit rapid (minutes to several hours) response in EC, and this response is associated with acute but reversible loss of endothelial barrier function (Fig. 1). The changes in transendothelial permeability are evoked by the pharmacological concentrations of 2ME (more than 100 nM), as opposed to the physiological concentrations (less than 100 nM)." (100nM = 0.1uM)
If the MTD model of cancer therapy, (that proved so successful in treating childhood leukemias,) applied to our current targeted, biologic approach, then this dose-limiting toxicity of 2ME2 would have clinical importance. However, nobody who knows what they are doing speaks in terms of MTD regimens when discussing antiangiogenic drug development, only the FDA reviewers do.
Best Regards,
C-Peptide
Re: Panzem coated stents.
A trial of Panzem coated stents is long overdue. J&J's corporate eyes should be lighting up with $$ at the prospect of owning them in partnership with EntreMed.
The problem with bare metal stents is that they stimulate a hypertrophic healing response that promotes restenosis of the vessel. The problem with the chemo-coated stents is that they are too good at suppressing healing, which prevents the formation of a normal endothelial lining, without which late thrombosis develops. A 2ME2 coated stent, using a less-toxic inhibitor of smooth muscle hyperproliferation, seems like a potential happy medium that deserves testing, even though the road to a product will be a very long one.
Best Regards,
C-Peptide
Re: Velcade/Panzem combo
I am certain that the rationale for the Velcade+Panzem combination is exactly the molecular physiology you describe. I view proteasome inhibition as a fairly blunt instrument for attacking cancer, much in the way matrix-metalloprotease inhibition has been. (although its developers probably would not appreciate that particular comparison) It is a part of both pro-cancer and anti-cancer pathways, and it is not necessarily clear where the balance lies when you block it. Your example of HIF-1alpha is an excellent one, where the proteasome is actively preventing a major player in angiogenic transformation from being turned on.
Also, although Velcade is intended to poison cancer cells, all cells are exposed to it (although thankfully it doesn't cross the blood-brain barrier very much, where it's effect would likely be to greatly accelerate neurodegeneration.) As such, it is really just another chemotoxin. Pairing it with a drug like Panzem, which causes the non-cancer cells to become less supportive of tumor growth, is logical and consistent with the overall antiangiogenic cancer program of MJF.
Best Regards,
C-Peptide
OT: re: Schwarz Pharma
Schwarz Pharma was at one time the lead company in the development of therapeutic C-peptide for the complications of type-1 diabetes, in partnership with the small Swedish biotech "Creative Peptides", however they have abandoned the partnership and Creative Peptides appears to be going it alone. I view Creative Peptides as a cousin of EntreMed, as they are also developing an endogenous molecule for the treatment of a chronic disease. Their Chief Scientific Officer, Dr. John Wahren, is the world leader in research into therapeutic C-peptide, as a review of the literature will show. About seven years ago I met with him to see if I could facilitate a clinical trial of C-peptide in Boston, but the time was not yet right. Schwarz thought they could improve on natural C-peptide with a synthetic analogue, but the project was abandoned. I owe my on-line name in large part to Dr. Wahren's research in to this missing part of hormone replacement therapy in type-1 diabetes.
Best Regards,
C-Peptide
Great post, George. Thanks. EOM
Also, let's not forget that doxycycline is antiangiogenic by itself, a fact which curiously gets no mention in the paper.
Refs:
1) Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJ. Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline.Chest. 2003 Nov;124(5):2017-22.
http://www.chestjournal.org/cgi/content/full/124/5/2017
2) Gilbertson-Beadling S, Powers EA, Stamp-Cole M, Scott PS, Wallace J, Copland G, Petzold M, Mitchell M, Ledbetter S, Poorman R, Wilks JW, Fisher C The tetracycline analogues minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent manner. Cancer Chemother Pharmacol 36:418 (1995)