Finding low-cost solutions neglected by the pharmaceutical industry.

Breast cancer prevention, and animal sterilization (dual applicability):

February 10, 2009 (also see update below):

Parsemus Foundation is involved with the effort to find a nonsurgical sterilant for pet and stray dogs (and cats), and it turns out that the current standard for sterilization-- removing both the uterus and the ovaries-- is quite detrimental to female dogs' long-term health in terms of increased risk of thyroid problems, incontinence, geriatric cognitive impairment, bone cancer, behavioral changes, etc.  We would like the veterinary community, and those seeking a nonsurgical sterilant, to be open to simple hysterectomy (taking out the uterus but leaving the ovaries) or to a non-hormone-eliminating nonsurgical approach should one be developed, but the 20% mammary tumor incidence for female dogs that retain their ovaries is a stumbling block.  Even though only half of those tumors will be malignant and only half of that half will metastasize or return, it is understandably a major concern.

With this in mind, in mid-December 2008 the foundation's director of medical research programs called Dr. Rajkumar Lakshmanaswamy, who is conducting a rodent breast cancer study with foundation funding, asking "Isn't there something that could be done about these high tumor rates?" (vs. near-zero mammary tumor rates for dogs with their ovaries removed).  "Can you think of anything, anything at all?"

In brainstorming, Dr. Lakshmanaswamy mentioned that some laboratories inject alcohol into the mammary ducts of rodents to clear out the fat pads before implanting human tissue, resulting in permanent ablation.  This seemed like just the ticket.  Why not do the same thing in dogs?  But a few questions arose immediately: Could this work in dogs as well as in rodents?  Are the dog teats structured the same way as rodent teats?  Would it be practical in dogs, or too time-consuming and/or tricky, to find the duct openings?  And finally, could this also work in high-risk women (for example, BRCA carriers) as an alternative to prophylactic mastectomy, and if not, why not?

On asking around more, the foundation's medical director was told that in rodents and dogs, there is one duct opening per teat, whereas in humans they are all gathered into the two nipples.  Furthermore, in rodents, injecting the first two teats apparently does most of the job, making the procedure easier.  On the other hand, part of what makes the procedure tricky on rodents is the extremely small scale, which is not such a problem in dogs and women.  So clearly it would be challenging procedure, but perhaps in dogs not much more time-consuming than the alternative, which is surgical removal of the ovaries, and perhaps possible in women as well?

In early January 2009, Dr. Lakshmanaswamy promised to contact Dr. Susan Love about the foundation's questions, since Dr. Susan Love's research organization is recognized as the premier institution working on the intraductal approach to breast cancer.  They pioneered a technique of flushing saline through the breast ducts in an attempt to look for cancer and precancerous cells in the fluid when it came out.  It was determined that the person to talk to there was Dr. Saraswati Sukumar, and on January 16, 2009 Parsemus foundation e-mailed her, that Dr. Lakshmanaswamy had:

"...mentioned that laboratories frequently inject a solution into the mammary ducts of rodents to clear out the fat pads before implanting human tissue.  So, I want to know: would this be practical to do in dogs?  Rather than removing uterus and ovaries for sterilization, remove the uterus only and inject the mammary ducts at the same time to prevent mammary tumors?  And, while we're at it, would this be possible in high-risk women (for example, BRCA carriers) as an alternative to prophylactic mastectomy?"

It turns out that Dr. Sukumar had the same idea-- that ablation of the mammary tree could prevent breast cancer in high risk women-- back in 1995.  But though she tried many substances, she hadn't found one that caused permanent ablation, so she switched to a similar idea, injecting chemotherapy drugs instead for temporary (but presumably fairly long-term) protection.  This idea was going very well, she had patented it, and in fact she had already completed Phase I trials in women.

But for dogs, permanent ablation would be better (and for some women too, depending on how long the chemo drugs' effect lasted).  Had she tried the same substance used on rodents, and had it not worked?  Inquiring minds want to know!  So the foundation wrote on January 20, "What led you to move from injecting ablation drugs (as done by Michael Gould et al.) to injecting chemo drugs?"  (Michael Gould at the University of Madison, Wisconsin was the one who had published the technique Dr. Lakshmanaswamy was using on rats).  It turned out, in an e-mail reply the next day, that Dr. Sukumar hadn't been aware of Dr. Gould's work with ablating drugs.  She had tried many permanent ablating agents, but none worked because of the gland's ability to regenerate-- so she switched to the idea of cleaning out the ductal system rather than ablating it.

But two questions remained: had alcohol (what Gould used) been one of the things she tried?  And why had Gould himself not pursued it?  To answer the second question, on January 20 the foundation spoke with Dr. Gould.  He clarified that a retired colleague, Kelly Clifton, had actually been the first one to use the technique, but had, he believed, never published it.  And, why did they not pursue the technique?  Because one, they figured it wouldn't work that well in humans what with all the multiple ducts, and two, if there were already hyperproliferation of cells (i.e. chunks of cancer), the masses of cells would block the fluid and not reach any cancers beyond it.  So they moved on.  Which seemed a shame, since the multiple ducts are a pain to find and inject but not the end of the world (certainly better than having to do a mastectomy), and Dr. Sukumar's work with injecting chemo drugs shows that if there are already lumps, you can inject chemo drugs multiple times until you dissolve enough of the lumps for the fluid to get around to the rest of the ductal structures downstream.

The final question remaining, then: Had alcohol/ ethanol been one of the things Dr. Sukumar tried?  The foundation spoke with another researcher at Dr. Susan Love's research institute, Dr. Dixie Mills, on February 5, who said it wasn't, but that she'd check with Dr. Love, and the foundation followed up with an e-mail asking "I look forward to hearing from Susan whether anyone has tried alcohol (as published by Michael Gould et al. and used by Raj Lakshmanaswamy) as a permanent ablation agent.  Is that one of the agents that Sara Sukumar tried that didn't work?"

So it appears that nobody has thought to try alcohol/ethanol for permanent ablation in dogs and humans (and other mammals) as is done in the lab with rodents, although it will become more clear at the conference on intraductal research later this month.  Parsemus Foundation looks forward to pursuing this possibility if, as it appears, it has not been done in larger mammals yet.  We hope to team with researchers who wish to test whether it will work in larger animals (dogs) with the goal of being used along with simple hysterectomy (or a future nonhormonal sterilant) to provide a means of sterilization which is less detrimental to long-term health than the current standard, ovariohysterectomy; and eventually to test whether intraductal alcohol/ ethanol injection can be used in humans as well, as an alternative to prophylactic mastectomy.

May 26, 2009 Update:

The answer that came out of the conference wasn’t completely clear, but one thing that was clear was that Dr. Sukumar did try alcohol, in mice, and saw ductal regrowth in 4 or 5 weeks.  But mice are not the same as rats, and rats are more similar to humans in terms of breast structure and functioning.

There’s an additional twist.  Dr. Sukumar’s studies on injecting chemo drugs are going well.  In fact, she thinks that even though she sees some ductal regrowth, it might, just might, be a long-term or permanent method anyway.  Why?  Because the few ducts that grow back don’t have many stem cells, and as we know now, stem cells are really important.  She describes the branches that grow back as like bare winter branches instead of spring branches.  But couldn’t the same be true of the branches that grew back when she tried alcohol?  Back when she tried alcohol in the 1990’s, people weren’t testing for stem cells.

We discussed this news, and Dr. Lakshmanaswamy, who is doing the breast cancer treatment study with foundation funding, thought the question was important enough to at least try it out in a few rats.  It seems to have gone quite well, but it’s too soon to get excited before trying it on a few more rats, and rats of various ages.

October 2009 Update:

It worked in the second round of rats too-- at least out to 6 weeks (which is a long time in a rat’s life).  Stay tuned for a third set to be sure.

February 2010 update:

It worked, it worked! The wiping out of the buds was not 100%, but pretty darn good at more than 80% of them with no regrowth. Dr. Lakshmanaswamy will now conduct the study again in larger groups of animals for publication. We encourage other teams to also try this research.

December 11, 2010 update:

On Thursday this week (December 9, 2010), Parsemus Foundation’s director met with a team of breast surgeons at IPGMER-SSKM Hospital (a government hospital) in Kolkata, India. The team was introduced to Parsemus Foundation by our Kolkata colleague working on nonsurgical male animal sterilization, Dr. Kuladip Jana; in a series of e-mails since February 28, 2010, the foundation has been discussing this idea with Dr. Jana. On April 7, 2010 the foundation’s director sent him the link to this web page to pass along, and on June 12, 2010 sent him a detailed discussion of the idea, and a photo from Dr. Lakshmanaswamy’s work, to pass along.

The good news: the team in India is interested, thinks it’s a good idea, and is going to apply for permission for a clinical trial! It was a meeting of the minds: Dr. Sarkar and colleagues were enthusiastic, had good critical questions (regarding how to avoid scarring of the nipple section of the duct, for example), and even had an idea for a further use of the idea: in benign breast problems. These abscesses etc. often bleed or ooze, and the only current therapy is surgical removal.

February 25, 2011 update:

No news from the Kolkata researchers; we’ll see whether that study happens.  However, good news from the Dr. Susan Love intraductal breast cancer conference going on right now: a team that has done clinical trials of the intraductal chemo approach (from Johns Hopkins) and a team that is wanting to study the effect on stem cells of intraductal treatment in mice (from the university of Utrecht in the Netherlands) have decided to collaborate. The team from Utrecht is interested in looking at alternatives to using chemo, since although it is a very small dose, treating healthy women with a drug that is known to increase the risk of leukemia presents an ethical dilemma.  Meanwhile, Parsemus Foundation is interested in testing alcohol and the sclerosant used in varicose veins in humans (Sotradecol or Polidocanol) in a dog with mammary tumors. 

There are lots of questions to be answered: Which drug is best?  How well does it work, if it works?  How long does it last?  Does it scar the ducts in such a way that makes future imaging and monitoring difficult? But things are looking up for the non-chemo intraductal treatment approach, and some of these questions may get answered.