Mathematical model of dual targetting cancer therapy

data based on melanoma.
Title:  Evolution dynamics of Cancer in response to targetted combination therapy.
The word "cure" actually appears here.    Though it may not apply to BC but the logic used is generally applicable and fairly interesting:
http://elife.elifesciences.org/content/2/e00747


Another article on heterogeneity of breast cancer from serum CTC:

J Intern Med. 2013 Aug;274(2):137-43. doi: 10.1111/joim.12047.

Circulating tumour cells: insights into tumour heterogeneity.

http://www.ncbi.nlm.nih.gov/pubmed/23844916
http://onlinelibrary.wiley.com/doi/10.1111/joim.12047/full


Another  article on the history of "Cell Kill" Adjuvant chemotherapy approaches of last 50 years, and inflammation-cancer link

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691519/

"DIGGING DEEPER: GROWTH PARAMETERS OF SOLID TUMORS CAUSE CHEMOTHERAPY RESISTANCE"

Nature's review of targetted BC medicine in clinical trials

Article in Nature:

"Emerging targeted agents in metastatic breast cancer"

Dimitrios Zardavas, José Baselga & Martine Piccart

Abstract

The same article has list of targetted medicine for drugs targetting microenvironment:
http://www.nature.com/nrclinonc/journal/v10/n4/fig_tab/nrclinonc.2013.29_T3.html

targetting BC cells in general:
http://www.nature.com/nrclinonc/journal/v10/n4/fig_tab/nrclinonc.2013.29_T1.html

targetting BC stem cells:
http://www.nature.com/nrclinonc/journal/v10/n4/fig_tab/nrclinonc.2013.29_T2.html


Even a result table for trials which has been completed:
http://www.nature.com/nrclinonc/journal/v10/n4/fig_tab/nrclinonc.2013.29_T4.html

Add up CR+PR+SD divide it with total n to get how good early results are.   Unfortunately no progression free survival information on the table.    A  cursory look at the table tells me the best, by head and legs are palbociclib for ER+ women with (PR+SD = 26 among 34 patients):

Letrozole ± PD 033299181

CDK1, CDK6

These are very interesting especially if they work for TN women, or could figure out accurate dx test to identify the people who might benefit better:

Cabozantinib222

MET, VEGFR2

Dovitinib60

FGFR1, VEGFR, PDGFRβ, KIT, FLT3

Vorinostat (+ ixabepilone)225

HDAC

I

36

All

All

2

6

16

Bosutinib231

SRC

II

73

All

Chemotherapy and/or hormone therapy

0

4

24

BKM120217	PI3K	I	9	All	Any	0	1	5
BKM120 (+ letrozole)218	PI3K	I	51	ER+/HER2–	AI	1	1	13

If someone's interested in any of these products, go back to Table 1 or table 2 or table 3, look for the other drugs with similar targets.    For example, if you are interested in PD 0332991 (palbociclib), go back to table 1 to look for other CDK targetting compounds.   Law of economics would suggest that those drugs will compete well and/or completement well with palbociclib.   No guarantee of course.

(Clinical Trial Conjecture I: The Conjecture of Achilles Heel:   As soon as someone proved that Achilles has a weakness in his heel, all the arrows from Troy's side is gonna go to the heel until Achilles, the invincible becomes vincible and his heel will look like porcupine.)

Notice also the drugs for whom the results are not so good or even abysmal.    Some are not good but has Complete response, that's still interesting.   Some may need to pair up with other drugs to perform well.   Some may need better diagnostic test to target better.     Remember HIV became treatable with a drug cocktail and cancer may be treatable too from a targetted drug cocktail.   So not to write any out, but a lot of work needs to be done if so many phase I/II trials are not turning out gold.  

There are probably many more drugs whose results are not in yet, or are dropped due to poor results, poor recruitment or for other technical or business reasons.     That is the invisible story of breast canc er clinical research.   We need more open data, more better designed drug clinical tests for new agents.

Natada in inspire shared these:
http://www.inspire.com/groups/advanced-breast-cancer/discussion/targetd-therapy-clinical-trial-for-breast-cancer-stem-cells-and-mbc/


Nice figure here:
http://www.nature.com/nrclinonc/journal/v10/n4/fig_tab/nrclinonc.2013.29_F1.html#figure-title
http://www.nature.com/nrclinonc/journal/v10/n4/fig_tab/nrclinonc.2013.29_F2.html

I might as well go into the Clinical Trial Conjecture II:
The Conjecture of Innovation being proportional to iteration speed:   The shorter time between lab bench to FDA approval, the faster the disease will get an effective cure.  and vice versa.

Comment:  neoadjuvant trials like ISPY-2 are going to accelerate the pace of BC innovation
http://clinicaltrials.gov/show/NCT01042379


and the Breast Cancer Clinical Trial Conjecture III:
The Conjecture of Good being the Enemy of the Best:  Adjuvant usage of ok drugs for early stage breast cancer may save lives, but they reduce the incentive for actual great drugs that cures late stage breast cancer.

Comment: This is caused by the unique character of breast cancer where early stage breast cancer rarely kills but are extremely common, yet because late stage breast cancer remains a killer, there are vastly more incentive to develop ok drugs for adjuvant use, vs great drugs for late stage bc patients.   It seems a lot of pharma would rather repurpose a proven ok cancer drug (developed for a different cancer), spend 10 years and 100s of millions to test its efficacy for breast cancer in adjuvant settings, rather than starting from scratch on new drugs that could potentially cure MBC.    You could argue the latter is more risky, or you could argue that the former gets better pay-off in adjuvant use on less risk.

HR+ breast cancer flipping biomarkers

I have reason to suspect HR+ breast cancer (even stage IVers) is going to get a cure (90+% 5 year survivability) pretty soon, within a few years.    But cancer is an evolutionary disease.   So I'm interested in understanding the phenomenon of HR+ BC flipping into triple negative type BC.

http://breast-cancer-research.com/content/14/3/r71



http://www.medscape.com/viewarticle/805441_4

Total of 11 triple negative patients.  5 of whom were stage III at start of study.   6 of whom were either NED stage IV or maybe stage II.    Total of 2 relapsed.   Very small study.

Quote from this article:  To gain a better understanding of the targets of TM, we measured circulating markers of angiogenesis. SDF1 and its receptor CXCR4, involved in angiogenesis and metastatic progression, may have a role in EPC recruitment.^[36,37] In breast cancer patients, expression of SDF1 has been inversely correlated with survival.^[38] In our study, SDF1 decreased with copper depletion but increased before relapse. Likewise, MMPs increased in patients before relapse. MMPs regulate tumor growth and invasion^[36] and provide a permissive bone marrow niche to facilitate mobilization of progenitor cells.^[39] Our observations suggest that SDF1 and MMPs may have important roles in metastatic progression.

Though a randomized clinical trial is necessary to assess survival, efficacy measures were promising. Of 11 triple-negative patients on study, only 2 relapsed. One patient did not adequately copper-deplete despite incremental dose increases. The other patient progressed within 2 months of TM therapy, suggesting that active neoangiogenesis was occurring at the time of enrollment, which could not be halted due to delayed effects of copper depletion. We are cautiously optimistic about the low incidence of relapse and have extended the study to 6 years in selected patients. Two stage-4 NED triple-negative patients remain disease-free at 65 and 49 months on TM therapy, which is encouraging given the dismal median survival of 9 months in metastatic triple-negative patients

http://www.ncbi.nlm.nih.gov/pubmed/23686707

http://www.ncbi.nlm.nih.gov/pubmed/22825030

http://www.ncbi.nlm.nih.gov/pubmed/22510516



I'm reading this with interest because ovarian cancer is linked and related to some type of TN breast cancer
http://www.cancernetwork.com/ovarian-cancer/content/article/10165/2148722

Should Cancer Clinical Trial Data be Open Sourced?

Every year hundreds of new agents are touted as potential cure for metastatic breast cancer and other deadly cancers.   Few got into early stage human trials often by small startup companies.   Some do well, some do ok, some do badly.     Big Pharmas could afford to buy dozens of these small startup companies.   And mostly these new agents are never heard from again.  The public has no idea which ones do well, ok, or badly.  These results were sealed,  should they be somehow accessible to public?   

http://www.nytimes.com/2013/06/30/business/breaking-the-seal-on-drug-research.html?pagewanted=all

Several related issues about metastatic breast cancer funding and drug development are discussed here:

http://community.breastcancer.org/forum/73/topic/806626?page=2#idx_45

Etacstil was once a promising breast cancer drug that performed ok or better in early stage human trial, but the company was acquired by BMS, and its early stage human trial's data was never published.   When its development and clinical trial was abandoned and existant tablets destroyed by BMS, patients who were doing well on that drug sued to try to stay on the drug, but to this day, results on its performance IS NOT accessible by public:

http://community.breastcancer.org/forum/8/topic/806200

This movement towards data openness started in Flu treatment, but will not end there.   

Also in today's news, another *attempted* acquisition of a big cancer drug maker onyx by other even bigger drug maker amgen.   How does drug development for MBC and other deadly cancers changes with this kind of consolidation going on all the time?   Which project (on either side) will live, which project will die?   What happens to the acquired clinical trial data under the new overlord?   

http://www.latimes.com/business/money/la-fi-mo-onyx-pharmaceutical-amgen-20130701,0,2996281.story

Big Pharma, little pharma are like any other business.   When the public hold out money without asking questions or putting in check/balances, it will ALWAYS be taken advantage of.

My question is:

How should we help in finding a metastatic breast cancer cure?   What change should we make in our laws and healthcare strategy?   Who should we recruit to make such changes?   FTC and/or  FDA?  researchers?  economists?  computer geeks?  media?

http://www.xconomy.com/national/2013/07/29/pharma-fails-credibility-test-misses-opportunity-on-transparency/?utm_source=rss&utm_medium=rss&utm_campaign=pharma-fails-credibility-test-misses-opportunity-on-transparency

Interesting news this week

Silver makes antibiotics much more effective:
http://www.scientificamerican.com/article.cfm?id=silver-makes-antibiotics-thousands-of-times-more-effective

Osteoporosis Drug Stops Growth of Breast Cancer Cells, Even in Resistant Tumors

http://community.breastcancer.org/forum/8/topic/806200

This is preclinical.  Some interesting comments by the author of bazedoxifene study, mentions other SERD (like Faslodex) that actually tested well in early clinical trials 10 years ago, but was shut down.

"about 10 years ago our lab identified and developed another SERD that is just as effective in vitro, could be administered orally, worked great in animal models, and, when Dupont took it into a small investigator initiated trial, worked well even in patients who had progressed during therapies targeting estrogen receptor.  So well, in fact, that when BMS bought Dupont and assumed that a paint company knew nothing about healthcare and closed the trial, the patients' Drs sued to keep them on the trial.  BMS responded by destroying 4 million tablets."     I'm trying to figure out that little bit of history.

Anti Cancer goo secreted by naked Mole Rats  Pretty interesting:

http://www.medicalnewstoday.com/articles/262236.php

CFI-400945 is applying for clinical trial:

http://life.nationalpost.com/2013/06/18/breakthrough-anti-cancer-drug-takes-direct-aim-at-tumours-canadian-u-s-researchers-say/

This drug is from the same UCLA lab (Dr Slamon) that gives us Herceptin and Palbociclib.   If this drug and other drugs from this UCLA Canadian Chinese partnership are any thing like Herceptin or Palbociclib, then, well, maybe i could stop writing this blog happily.  

Quote from this article:

“I cannot promise you that it will work,” he said of the experimental drug, “because in advanced human cancer there are many other questions that we have not got answers to.

“But we promise you this is the beginning,” said Mak, his voice breaking with emotion. “There will be another drug that we will be filing for [approval] next year — and next year and next year — until we get this done.”

It’s taken about 100 researchers in Toronto, L.A. and China to develop CFI-400945 at a cost so far of about $40-million, said Mak, standing beside a copy of the 4,300-page application submitted to the FDA, the height of about five Toronto phone books.

That money all came from non-government sources, raised through 10 years of fundraising walks to end women’s cancers, and private and corporate donations.

...

http://www.ncbi.nlm.nih.gov/pubmed/23829549

   

  

Supreme Court Strikes Down Gene Patents

Nature can not be patented:
http://www.boston.com/business/technology/2013/06/13/court-says-human-genes-cannot-patented/56BCnX2hTvDXSOedSkOy0N/story.html

But some processes could:
http://www.startribune.com/lifestyle/health/211446711.html

"However, Jeffrey Rosenfeld, a researcher and assistant professor at the University of Medicine and Dentistry of New Jersey, said the ruling is good news for researchers, who now will be able to sequence genes to try to better understand diseases and to create new treatments — without fear of being sued by companies such as Myriad.

"Their monopoly is gone. The method patents basically are completely irrelevant," Rosenfeld said.

He said diagnostic testing companies now could sequence genes linked to breast cancer or other diseases and use the information to develop diagnostic tests that use different methods than Myriad's. Likewise, he said, "scientists can now research freely without fear of being sued."

Sad really.   Is the gene patent troll problem as bad as in software?  

Rucaparib Parp Inhibitor Showing High Disease Control Rate In Early Test

http://meetinglibrary.asco.org/content/115538-132

Disease control >12 week