Patient-Specific Cancer Cell Lines Designed To Predict Chemotherapy Sensitivity

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Patient-Specific Cancer Cell Lines Designed To Predict Chemotherapy Sensitivity

by Gdpawel on Wed Feb 20, 2013 03:47 AM

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In laboratory studies, scientists at the Johns Hopkins Kimmel Cancer Center have developed a way to personalize chemotherapy drug selection for cancer patients by using cell lines created from their own tumors. 

If the technique is successful in further studies, it could replace current laboratory tests to optimize drug selection that have proven technically challenging, of limited use, and slow, the researchers say. 

Oncologists typically choose anticancer drugs based on the affected organs' location and/or the appearance and activity of cancer cells when viewed under a microscope. Some companies offer commercial tests on surgically removed tumors using a small number of anticancer drugs. But Anirban Maitra, MBBS, professor of pathology and oncology at the Johns Hopkins University School of Medicine, says the tissue samples used in such tests may have been injured by anesthetic drugs or shipping to a lab, compromising test results. 

By contrast, he says "our cell lines better and more accurately represent the tumors, and can be tested against any drug library in the world to see if the cancer is responsive." 

The Johns Hopkins scientists developed their test-worthy cell lines by injecting human pancreatic and ovarian tumor cells into mice genetically engineered to favor tumor growth. Once tumors grew to one centimeter in diameter in the mice, the scientists transferred the tumors to culture flasks for additional studies and tests with anticancer drugs. 

In one experiment, they successfully pinpointed the two anticancer drugs from among more than 3,000 that were the most effective in killing cells in one of the pancreatic cancer cell lines. A report on the success was published online recently in the journal Clinical Cancer Research. 

The new method was designed to overcome one of the central problems of growing human tumor cell lines in a laboratory dish -- namely the tendency of noncancerous cells in a tumor to overgrow cancerous ones, says James Eshleman, M.D., Ph.D., professor of pathology and oncology and associate director of the Molecular Diagnostics Laboratory at Johns Hopkins. As a consequence, it has not been possible to conventionally grow cell lines for some cancers. Still other cell lines, Eshleman says, don't reflect the full spectrum of disease. 

To solve the problem of overcrowding by noncancerous cells, Maitra and Eshleman bred genetically engineered mice that replace the noncancerous cells with mouse cells that can be destroyed by chemicals, leaving pure human tumor cells for study. 

"Our technique allows us to produce cell lines where they don't now exist, where more lines are needed, or where there is a particularly rare or biologically distinctive patient we want to study," says Eshleman. 

In its proof of concept research, the Johns Hopkins team created three pancreatic ductal adenocarcinoma cell lines and one ovarian cancer cell line. They then tested one of the pancreatic cancer cell lines (called Panc502) against the Johns Hopkins Drug Library of 3,131 drugs, identifying tumor cells most responsive to the anticancer drugs digitoxin and nogalamycin. 

For 30 days, they watched the effects in living mice of the two drugs and a control medicine on tumors grown from implanted cells derived from Panc502 and an additional pancreatic cell line, Panc410. They measured the size of tumors twice a week. Both drugs demonstrated more activity in reducing the tumor appearance and size in Panc502 than in Panc410, supporting the notion that the cell line technology may better predict sensitivity to the two drugs. 

The investigators have given one type of their genetically engineered mice to The Jackson Laboratory in Bar Harbor, ME, a mouse genetics research facility, for breeding and distribution to other laboratories and are looking to partner with a company to distribute two other types.

References:

Study co-authors were Hirohiko Kamiyama, Sherri Rauenzahn, Joong Sup Shim, Collins A. Karikari, Georg Feldmann, Li Hua, Mihoko Kamiyama, F. William Schuler, Ming-Tseh Lin, Robert M. Beaty, Balasubramanyam Karanam, Hong Liang, Michael E. Mullendore, Guanglan Mo, Manuel Hidalgo, Elizabeth Jaffee, Ralph H. Hruban, Richard B. S. Roden, Antonio Jimeno, and Jun O. Liu, of Hopkins; and H. A. Jinnah of Emory University School of Medicine in Atlanta. 

The work was supported by the National Institutes of Health, National Cancer Institute (CA130938, CA62924 and CA122581), the Sol Goldman Pancreatic Cancer Research Center, the Stewart Trust Fund, the Lustgarten Foundation, the Mary Lou Wootton Pancreatic Pancreatic Cancer Research Fund, the Michael Rolfe Pancreatic Cancer Foundation and the HERA Foundation. 

Rauenzahn, Maitra and Eshleman may receive royalty payments if the mice are licensed, and Eshleman is an advisory board member for Roche Molecular Diagnostics. These relationships have been disclosed and are under the management of the Johns Hopkins University School of Medicine Conflict of Interest Committee.

Citation: Johns Hopkins Medicine. "Patient-Specific Cancer Cell Lines Designed To Predict Chemotherapy Sensitivity." Medical News Today. MediLexicon, Intl., 19 Feb. 2013

RE: Patient-Specific Biomarker Information to Generate a Treatment Approach

by shelby1 on Wed Feb 20, 2013 02:23 PM

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I think you are saying that to cure cancer one must make cancer cells die when they are suppose to as a "normal" cell.  Research into cell lines may produce just the pathway to "make' those errant cells die because there is obviously something wrong with the cancer cells. Whether via  live tumor or cell lines, the act of researching why cells don't die does need to be explored. In the meantime staying alive to see that day may be the best way chemo can help both the patient and the researcher!

RE: Patient-Specific Biomarker Information to Generate a Treatment Approach

by maxxschiken on Wed Feb 20, 2013 02:56 PM

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On Feb 20, 2013 2:23 PM shelby1 wrote:

I think you are saying that to cure cancer one must make cancer cells die when they are suppose to as a "normal" cell.  Research into cell lines may produce just the pathway to "make' those errant cells die because there is obviously something wrong with the cancer cells. Whether via  live tumor or cell lines, the act of researching why cells don't die does need to be explored. In the meantime staying alive to see that day may be the best way chemo can help both the patient and the researcher!

While it is true "staying alive to see that day may be the best way chemo can help both the patient and the researcher," unfortunately there are too many who ultimately expire much too soon after making the wrong choice in a chemotherapy option, finding themselves poisoned to the point they are too weak and are no longer able to tolerate ANY more treatment alternatives! 

This happened in 2010 with my co-worker who was diagnosed with inoperable stage 4 pc with liver mets.  Mid-40's and physically fit, he made a very educated decision to begin treatment with folfirinox, a relatively "new standard" of treatment with greater results than the current standard of that time, Gemzar.  He was hospitalized during the very first 4-hour infusion and almost died.  He expired 4 months later.  Would he have lived longer if he had gone with a less toxic combination of drugs?  Maybe... maybe not.  But the fact is he never got a chance to.

I believe this type of research will ultimately save many lives. 

RE: Patient-Specific Biomarker Information to Generate a Treatment Approach

by shelby1 on Wed Feb 20, 2013 03:30 PM

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I am really sorry about your co-worker and the bad experience with Folfirinox.But you are right about it  being the new standard as it is now and has helped many others to live longer. Gemzar is only the beginning of the chemo regimes  for PC and when that fails there are many other tries from there. Many new things since 2010 have come along, we know because we have been at this since 2008 when there was only Gemzar. and radiation.. Everyone reacts differently to any medication and I am trully sorry about your co-worker.  I think it depends on the type of pancreatic cancer and whether it is metastactic or not. Your co-worker had mets to the liver and at the time Folfirinox was the only chemo option. He made a "very educated decision" that unfortunetly didn't work for him.  I think staying alive while research is ongoing and doing clinical trials is everyone's chance because there are so few chances with PC.  We can not do Folfirinox because of low blood counts but we are doing something else which is more than  was available back in 2010. These decisions are something patients make with their doctors guideance so I wonder if they are  any"wrong" decisions if there is an unforeseen reaction. I really am sorry about your co-worker but Folfirinox does help others.    

RE: Patient-Specific Biomarker Information to Generate a Treatment Approach

by Kjohnchas on Wed Feb 20, 2013 04:28 PM

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My husband has PC cancer after 6 weeks of radiation he is now on cisplatin and etoposide for how long not sure has treatment every 21 days but last week was in hospital 6 days because of WBC and fever and than enzymes were not good.

RE: Patient-Specific Biomarker Information to Generate a Treatment Approach

by Gdpawel on Wed Feb 20, 2013 06:14 PM

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The needed change in the war-on-cancer will not be on the types of drugs being developed, but on the "understanding" of the drugs we have. The system is overloaded with drugs and underloaded with the wisdom and expertise for using them, on "individuals," not average populations.

Cancer patients usually undergo four or five courses of chemotherapy before medical oncologists can tell whether the treatment is having an effect. By that time, the tumor may have grown so large that it is too late to switch to another chemotherapy regimen or the patient may be so weakened by the treatment that trying another approach is not immediately feasible.

Medical oncologists treat a lot of patients but they don't know going into treatment if it's going to work. A major obstacle in controlling cancer growth and metastasis in patients is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice.

It would be highly desirable to know what drugs are effective against particular cancer cells before these cytotoxic agents are systemically administered into the body. Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data.

In a recent article in Biotechniques, "Will the Real Cancer Cell Please Stand Up," the value of using cancer cell-lines for drug sensitivity investigation has come under fire. Cancer cells are not individual entities, but networks, a harmonic oscillation develops between tumor, stroma, vasculature and cytokines. In this mix, the cancer cell is but one piece of the puzzle.

Almost every anti-cancer drug now in use gained early traction through testing on cancer cell-lines. But now some researchers are calling for new models that can assay primary cancer cells directly from patients to sketch a more realistic molecular portrait of primary tumors.

http://www.biotechniques.com/news/Will-the-Real-Cancer-Cell-

RE: Patient-Specific Biomarker Information to Generate a Treatment Approach

by maxxschiken on Thu Feb 21, 2013 08:28 AM

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On Feb 20, 2013 3:30 PM shelby1 wrote:

I am really sorry about your co-worker and the bad experience with Folfirinox.But "" target="_blank" rel="nofollow">http://Folfirinox.But " target="_blank" rel="nofollow">Folfirinox.But you are right about it  being the new standard as it is now and has helped many others to live longer. Gemzar is only the beginning of the chemo regimes  for PC and when that fails there are many other tries from there. Many new things since 2010 have come along, we know because we have been at this since 2008 when there was only Gemzar. and radiation.. Everyone reacts differently to any medication and I am trully sorry about your co-worker.  I think it depends on the type of pancreatic cancer and whether it is metastactic or not. Your co-worker had mets to the liver and at the time Folfirinox was the only chemo option. He made a "very educated decision" that unfortunetly didn't work for him.  I think staying alive while research is ongoing and doing clinical trials is everyone's chance because there are so few chances with PC.  We can not do Folfirinox because of low blood counts but we are doing something else which is more than  was available back in 2010. These decisions are something patients make with their doctors guideance so I wonder if they are  any"wrong" decisions if there is an unforeseen reaction. I really am sorry about your co-worker but Folfirinox does help others.    

Indeed, folfirinox alone did the job for my wife with minimal side-effects and a great quality of life during treatments which began one month after diagnosis in July 2011 with inoperable stage 4 pc which metastisized to her liver.  It ended up being the perfect choice for her and her body.

After only 4 months of treatments the two spots measuring less than 1cm each on her liver disappeared and the 5cm tumor on the body of her pancreas shrank to a mere 4mm.  After an additional 6 months of treatments without any breaks for the entire 10 months/19 sessions/9.5 cycles of folfirinox her liver remained clear and the 4mm tumor became a scar tissue. She not only tolerated all those treatments but she embraced each and everyone of them, never wanting to miss one, be late for one or even skip one! 

She has not had any treatments/chemo/nothing but metformin to manage type 2 diabetes since the end of May 2012.  Her blood work to monitor CA19-9 every other month have been stable under 35 and her quarterly CTscans in June, September and December 2012 have shown no evidence of new or progressive metastatic disease and no tumor recurrence.  Her next CT is scheduled for March.

10 months in remission has allowed her to build up her stamina.  On Feb 2, she re-instated her fitness center membership and works out 2 hours daily with strength endurance, cardiovascular and weight lift training.  She is pretty much back to her fitness level prior to diagnosis.  The objective is to prepare her body both physically and mentally for whatever the future holds for her. 

She's an amazing woman who literally took the prognosis of this disease (4 months of life without treatment and maybe 6-8 months of life maximum if she could tolerate chemo) and proved to her oncologist and consultants at UCSF that in her case, they were wrong. 

Indeed, folfirinox was the perfect choice for her.     

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