In the Lab

On Cancer: Study Clarifies How Bladder Cancer Treatment Works

By Jim Stallard, MA, Writer/Editor  |  Friday, February 1, 2013
Pictured: BCG Bladder cancer cells infected with BCG (shown in green), an effective treatment for early-stage bladder cancer. The same genetic mutations that cause bladder cancer also activate a mechanism in the cells that allows BCG to enter and destroy them.

Memorial Sloan Kettering researchers have shed light on how an important treatment for early-stage bladder cancer eradicates cancer cells. They also found evidence that the effectiveness of this bacterial treatment, called BCG therapy, may be determined partly by the presence of specific genetic mutations within cancer cells.

“This study shows that some of the same mutations causing bladder cancer also activate a process that allows the treatment to enter the cancer cells and destroy them,” says Gil Redelman-Sidi, an infectious diseases specialist who conducted the research together with physician-scientist Michael S. Glickman. “It raises the possibility that specific properties of a patient’s tumor cells might predict how well BCG therapy will work.”

The researchers, including Memorial Sloan Kettering physician-scientists and co-authors David B. Solit and Gopa Iyer, report this finding in the February 1 issue of Cancer Research.

Effective, But Mysterious

BCG (Bacillus Calmette-Guerin) is a weakened form of a bacterial pathogen that has been used widely as a vaccine for tuberculosis for nearly a century. Beginning in the 1950s, the late Memorial Sloan Kettering cancer immunologist Lloyd J. Old and other researchers began investigating BCG as a treatment for cancer, and clinical studies conducted at Memorial Sloan Kettering demonstrated the effectiveness of this therapy for early-stage bladder cancer.

Although BCG continues to be the preferred treatment for such cancers, it has not been clear how the pathogen invades the cancer cells and — once inside — leads to their destruction. Many researchers think BCG stimulates some form of antitumor immunity, but the exact mechanism has not been well understood. To add to the puzzle, approximately 30 percent of bladder cancer patients don’t respond to BCG treatment, and no test exists to predict which patients will be resistant.

“BCG is a mycobacterium — a type of bacteria usually taken in only by certain immune cells that are looking for invaders to destroy,” Dr. Glickman explains. “Mycobacteria are not equipped with a means to force their way into other kinds of cells, so it has been a bit of a mystery how BCG enters bladder cancer cells and why certain cells resist the treatment.”

Mutations Open the Door

An important insight into what makes the entry of BCG into cells possible arose from a collaboration between the Glickman lab and Memorial Sloan Kettering cell biologist Xuejun Jiang. In June 2012, this team reported in the Journal of Biological Chemistry that cancer cells with mutations in the gene PTEN are highly susceptible to mycobacterial infection. The PTEN protein normally acts as a tumor suppressor; impaired PTEN function appears to increase a cell’s vulnerability to becoming cancerous and also to mycobacterial infection.

To investigate whether this correlation holds true in bladder cancer cells, Drs. Redelman-Sidi, Glickman, and colleagues treated six distinct cell lines — groups of genetically identical cells developed from a single cell — with BCG and measured the degree to which the BCG bacterium was taken up by the cells.

They discovered that the cell lines that most readily took up BCG contained one of several cancer-causing mutations, including mutations in PTEN, known to be involved in the onset of bladder cancer. The cell lines resistant to BCG did not have these particular mutations, but they could be converted to BCG-receptive cells if the mutations were induced. Moreover, these converted cells readily took up BCG via a pathway different from the one BCG usually employs to enter immune cells.

“These mutations activate a mechanism in the bladder cancer cells that allows BCG to enter and destroy them,” Dr. Glickman says.

Moving from the Lab to the Clinic

Dr. Glickman’s laboratory is now collaborating with urologic surgeon Bernard H. Bochner to explore the clinical implications of this discovery — particularly, whether analyzing a patient’s bladder cancer cells can reliably predict his or her responsiveness to BCG therapy.

With the support of a grant from The Society of MSKCC, Dr. Redelman-Sidi is trying to develop a lab test that would analyze urine samples, which usually contain cancer cells shed from the bladder. These cells could be tested both for their tendency to take up BCG and also for the presence of BCG-activating, cancer-causing mutations.

“This would allow us to screen early-stage patients routinely before starting BCG therapy to make sure it’s the best course of treatment,” Dr. Glickman says.

Dr. Redelman-Sidi’s work is supported by awards from the Lucille Castori Center for Microbes, Inflammation, and Cancer and from the Bladder Cancer Advocacy Network. The study reported in Cancer Research was supported by the Geoffrey Beene Cancer Research Center and the Starr Foundation.

Comments

Thank you for the insight on the continuing cancer research.

Thank you for your continuing research on Bladder Cancer. I am a two time survivor of Bladder Cancer and find your information very useful. PWK

I have been treated by my Urologist for a bladder condition that is "not cancer but would be if not treated" I am told. As I understand the medication which is instilled once a week for three successive weeks, is live tuberculin bacteria and interferon. I may be misunderstanding the medication or improperly describing the "mix". In any event I have been treated for a couple of years and have a series of three coming up in May. My question is whether my treatments are the same as you are describing or something different. Whatever it is it seems to be preventing the development of cancer. Just as a "by-the-way", I have survived Prostate (1997) colon (1998) and melanoma (2003). I also had a suspicious growth removed from my larynx that was similarly described as unknown, but not cancer but "probably would be if not removed." I am not undergoing any chemo nor have I except for 6-months following the colon resection.

Thank you for your comment. We encourage you to discuss this question with your urologist, or if you would like to make an appointment with a doctor at Memorial Sloan-Kettering, please call 800-525-2225.

I was diagnosed with kidney and bladder cancer in 2002. I have had BCG alsoThio Teppa. I did lose the kidney but am still doing fairly well with cystos and cancer cells taken out every 3 months or when needed.

I went through 3 years of BCG treatments and now have just one maintenance treatment a year. I do have some problems when I did have the treatments and also with the once a year treatment. But I feel being I have been clear of bladder cancer for three years it is well worth having the BCG treatments.

Thank you for your bladder cancer researc. Please keep on working, BC is one area that does not receive the public acknowledgement or support as do other cancers. I had a nephroureterectomy in 2011, had one turb for a bladder tumor immediately following the nephro. Am following BCG protoccol, on #15. So far over a year BC free. Please keep one with your reasearch .

Having had reappearing bladder polyps off and on for the last 10 years. After the first lifting (one canacerous polyp) 6 BCG infusions were prescriped - keeping me cancer free for many years. Having continued with bladderexams every 6 months.
The results of an excaminatipon in December 2012 showing, 4 Polyps grew back - one of them cancerous which were removed in January 2013. This time again 6 BCG were prescriped in 6 successive weeks. After the first, second and third infusion I noticed bleedings afterwards. My Urologist stopped the treatments. Now prescriping 3 "Mitomycin 40 mg infusions - free of complications. As in the previous years, periodic excaminations (every 6 months) kept my bladdercancer in check

cancer de utero e estadio 3 es posible curarlo?

Javier, el hospital Memorial Sloan-Kettering tiene un equipo de expertos multidiciplinarios disponible para ofrecer varios tratamientos para cáncer del útero, incluso sirugía, radiación, quemoterapia, terapia hormonal, y terapias investigacionales. Visita esta página para más información sobre este tipo de cáncer y estos tratamientos: http://www.mskcc.org/cancer-care/adult/endometrial-other-uterine. Para hacer una cita con uno de nuestros médicos, llame al 800-525-2225 o visita esta página: http://www.mskcc.org/cancer-care/appointment Gracias por su comentario.

My friend started the BCG treatment today for 6 weeks. His doctor said after the treatment he will do a cytoscopy to follow up on effectiveness. He doesn't believe he should have the treament every month. He believes if it doesn't work the first time treatment should be changed, however I hear people have many treatments through the years. Who's right?

Hilaria, we are not able to answer individual medical questions on our blog. If your friend would like to speak with a Memorial Sloan-Kettering physician about his treatment, he can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment for more information. Thank you for your comment.

Is BCG an active or inactive TB drug?

Robert, thank you for your comment. We consulted with Dr. Glickman who explained that BCG is an attenuated strain (bacterial derivative) of Mycobacterium bovis, which causes infection of cattle and, in the past, of humans. BCG was derived by growing M. bovis until it became less virulent, or weakened. The original intent of deriving BCG was as a vaccine for infection, not for therapy of Bladder Cancer. Therefore BCG is a living bacterium, although weakened from its parental bacterium. BCG does not use the Mycobacterium tuberculosis bacterium.

In July 2010 I had surgery for a single papillary high-grade bladder cancer tumor. I did the traditional BCG therapy with no problems and was clear on all of my cystos. In January 2013 my urologist said I had done so well that I could go 6 months now between cystos. I agreed but told him I still wanted a urine analysis every 3 months. He was fine with that. Today (6 months after my last cysto in January 2013) I got another all-clear on my cysto. This means that I have been tumor-free for 3 years now. My urologist now says I do not need to take any more BCG treatments--just the 3-month urine analysis and the 6-month cysto. My question is do you think it is okay to stop the BCG treatments (last treatment was January 2013)?

David, we are not able to answer individual medical questions on our blog. If you'd like to get a second opinion about your treatment from a Memorial Sloan-Kettering doctor, you can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment for more information. Thank you for your comment.

As a bladder cancer (transitional cell) patient, I've been treated (Seattle's Virginia Mason MC) with six infusions (one per week) of BCG, which turned out to be ineffective or maybe partially so. Is inducing PTEN protein mutations as a pretreatment for additional BCG available yet or is it still in laboratory status?

Thomas, thank you for your comment. We consulted with one of our physicians, Gopa Iyer and this is his response to your question:

Testing for PTEN status as a screening tool for predicting the efficacy of BCG therapy is still in laboratory testing. It would require large numbers of patient tumors to be tested and then correlated with BCG response to confirm this finding and we are not at that stage. Being able to induce PTEN mutations in tumors prior to BCG therapy is not feasible in patients yet.

I just began a 6 week series of BCG treatments. The second infusion is delayed by 6 days. How will that delay impact the treatment process?

Robert, we are unable to answer specific medical questions on our blog. If you would like to make an appointment with a Memorial Sloan-Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. For questions about bladder cancer treatment, you also can call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237).Thanks for your comment.

It still does not answer the question as to how it prevents recurrence in some patients; Once the BCG gets into the cancer cell and destroys them; How does it prevent new cancers from getting formed even if BCG is not given/

Ajay, thank you for your comment. We consulted with Dr. Glickman about this and he responded:

The commenter is correct that our study does not answer that question and the mechanism by which BCG prevents recurrences is not known, but is presumed to be immune. We hope to study these mechanisms in our future work.

I have been diagnosed with stage 2 bladder cancer. Next week I will start with a six week treatment with chemo and radiation at Sibley Hospital in Washington D.C. May I talk to someone there to get more information on this disease? Bladder removal and BCG have been discarded due to the advanced condition
Of the cancer into the muscle wall although it has not perforated through the wall
Which I understand would be Stage 3. Should i call to get more information?

Hi Davis, you can call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment for more information.
Also to learn more about treatment for bladder cancer, you can find out more at: http://www.mskcc.org/cancer-care/adult/bladder

Thank you for your comment.

What is known about the long-term and or permanent effects of BCG treatment on the healthy tissues of the bladder?

Dear Ben, here is a patient education summary with information about BCG, including facts about the drug's side effects: http://www.mskcc.org/cancer-care/patient-education/resources/bcg

For additional questions about bladder cancer treatment, you also can call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237).Thanks for your comment.

My husband is undergoing BCG now. I have had pneumonia numerous times in the past 10 years 3 in the last 2 years. ShoI get a boosterTB shoT? I have peripheral nueropathy and therefore a compromised immune system. I also would like to know what precautions we should take during intercourse? What other precautions should I be taking?

Cyndy, thank you for your comment. We consulted with our physicians about your concerns and these are their responses.

1) Although BCG is also used as a vaccine for TB, it is not given in the US. BCG is not TB and you can’t get TB from being exposed to BCG.
2) We don’t consider family members at risk for being infected with BCG because it is a weakened bacterium that is given to most of the world’s children and is very safe.
3) We do recommend condom use during the BCG treatment regimen.

Does eating, drinking or taking supplements impact BCG treatments?
Are there anythings to avoid, say caffeine, alcohol or sugar?
Are there any things that could help, like vitamin C or D or eating asparagus?
Thanks,

Mary, we are unable to answer specific medical questions on our blog. You can call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237) for more information about BCG. In addition, here is a patient education summary with some BCG information: http://www.mskcc.org/cancer-care/patient-education/resources/bcg

Thanks for your comment.

Had a turbo for t1 plus cis bladder cancer in 2011. I've had 19 bcg treatments in all and even though the dose it just 1/100th it is extremely painful for at least a day or two. Thankfully I'm cancer free and my treatments are now just 3 weeks once a year. My question is - because I seem to have such a painful reaction to bcg and I understand some don't find it very painful at all, do you think that maybe it is more effective in my case? Hope I've made sense!

Pamela, we are unable to answer specific medical questions on our blog. If you would like to make an appointment with a Memorial Sloan-Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thanks for your comment.

I had cysto last week, my doctor told me that it was low grade BC and no further investigation required except cysto afer 3 months.
Do I need BCG?

Anis, unfortunately we are unable to answer specific medical questions on our blog. If you would like to make an appointment with a Memorial Sloan-Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thanks for your comment.

My wife has bladder cancer and is due to begin bcg treatment next week. The article "Study Clarifies ---" was written 11 months ago. It mentions continuing work on a urine test to detect susceptibility to bcg. Are there more recent results available?
Thank you.

Leigh, we consulted with Gil Redelman-Sidi, one of the researcher-physicians mentioned in the story, and he provides this response:

"We are still in the early phases of development a urine test to predict response to BCG therapy. The test is not yet available in the clinic."

Thank you for your comment.

Thanks for your prompt reply to my question concerning a clinical test of urine to examine vulnerability to bcg. My wife would be willing to participate if desired. She is being treated in Kaiser-Permanente in South San Francisco, CA by Dr. Peter Lee a Urologist. Dr. Lee describes the cancer as being rare and unusually aggressive. I realize that we are 3,000 miles apart and understand that the distance may be prohibitive.
Thank you.

Leigh, since the test is still in the early phases of development, it is unlikely a clinical trial will be enrolling anytime soon, but you can check our clinical trials page periodically. You might also want to go to www.clinicaltrials.gov to find out if similar trials may be available at other centers, including possibly some that are closer to you.

Is there possible danger in BCG treatment for bladder cancer
for a patient who tested positive in skin test for TB?

Hi, Amanda, we send your inquiry to Dr. Glickman, who responded, "There is no danger of receiving BCG for bladder cancer in a patient with a positive skin test for TB."
Thanks for reaching out to us.

Thank you for informative and prompt reply.
One further query: would it make any difference in any future possible BCG treatment for my bladder cancer that the probable cause of my childhood positive skin test for TB was ingestion of bovine milk. The poor cow was slaughtered
when she was tested positive!

Amanda, thanks for your comment--the possible cause of your positive TB test would not make any difference. There would be no danger for receiving BCG treatment for bladder cancer.

My father was treated 30 years ago for bladder cancer he had one treatment with BCG. and cystoscope once a year. I have now been diagnosed with BC and on my 3rd treatment of 6 of BCG. After I will then have a cystscope every 3 months. My question is do you feel this is inherited? I have never been a smoker and female which is not the common scenario. Also my fathers doctor is still practicing would it be helpful for your research to see if there is a common Denominator between my fathers pathology report and mine?

Anne, the majority of all cancers, about 90 to 95 percent, are not inherited but occur randomly. If you’d like to speak to someone on our Clinical Genetics Service more about this, you can call 646-888-4050 or go to http://www.mskcc.org/cancer-care/hereditary-genetics for more information. Thank you for your comment and your offer to contribute to our research!

Can you tell me if it is common practice after a BCG treatment, to be given one antibiotic pill to help prevent infection?

Thank you,
Anne

Anne, thank you for your comment. We consulted with MSK medical oncologist Gopa Iyer, who responds:

It’s not a standard of care to give antibiotic prophylaxis with BCG therapy. I don’t believe the urologists here administer antibiotics to patients receiving BCG on a regular basis.

It's great that BCG has been effective for bladder cancer, but in the case of my husband, it only made matters. While removing a large kidney stone, the urologist found an extremely large cancerous bladder tumor,the size of an egg. He removed it and started him on successive BCG treatments, once a wk for 6 weeks. After the next cystoscope ,he now had more tumors. He had to remove them and then more BCG. It was an endless cycle of treatment and more surgeries with tumors multiplying and growing faster. This went on for two years, with us questioning the dr and asking for a second opinion. He said he was doing what would help, but I reminded him the def of insanity( doing the same thing over and over and expecting diff results) and asked about mytomycin-c. He said that didn't work, but a friend of ours was given that for his first bladder tumor, which was cancer, and his was gone with only that and never came back. We insisted on an oncologist and that dr recommended the mytomycin-c. He had 1 a week for 6 weeks with no reoccurrence ,and had 3 more later and has been cancer free for over a year and a half after having treatment that did not work for over two years. I wish the dr had listened to my pleas sooner, instead of insisting on trying the BCG over and over without good results. People need to be informed of alternative treatments that can work. Thank you for taking my comments.q

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