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Old 12-02-2014, 10:41 AM   #1
Lani
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Thumbs up Simple cheap drugs already approved vs. osteoporosis may prevent, reverse her2+breast

cancer

http://www.pnas.org/content/early/2014/11/26/1421422111

Widely Used Osteoporosis Drugs May Prevent Breast, Lung and Colon Cancers

NEW YORK – December 1, 2014 /Press Release/ ––
The most commonly used medications for osteoporosis worldwide, bisphosphonates, may also prevent certain kinds of lung, breast and colon cancers, according to two studies led by researchers at the Icahn School of Medicine at Mount Sinai and published today in the Proceedings of the National Academy of Sciences (PNAS).

Bisphosphonates had been associated by past studies with slowed tumor growth in some patients but not others, and the mechanism behind these patterns was unknown. In the studies published today, an international research team showed that bisphosphonates block the abnormal growth signals passed through the human EGF receptors (HER), including the forms of this protein family that make some tumors resistant to leading treatments. The connection between bisphosphonates and HER receptors was detected first in a genetic database analysis and confirmed in studies of human cancer cells and in mice.

“Our study reveals a newfound mechanism that may enable the use of bisphosphonates in the future treatment and prevention of the many lung, breast and colon cancers driven by the HER family of receptors,” said lead study author Mone Zaidi, MD, Professor of Medicine and of Structural and Chemical Biology within the Icahn School of Medicine at Mount Sinai, Director of the Mount Sinai Bone Program and a member of the Tisch Cancer Institute at Mount Sinai. “Having already been approved by the FDA as effective at preventing bone loss, and having a long track record of safety, these drugs could be quickly applied to cancer if we can confirm in clinical trials that this drug class also reduces cancer growth in people. It would be much more efficient than starting drug design from scratch.”

Of the two newly published PNAS papers, one describes the evidence that bisphosphonates block abnormal growth signals through HER family receptors, while the second examines the potential applications for this new mechanism: cancer prevention, combination with existing treatments, and use against treatment-resistant tumors.

Stop Abnormal Growth
The study results revolved around the human epidermal growth factor receptor (HER/EGFR) family, which consists of four types of transmembrane tyrosine kinase receptors: HER1, HER2, HER3, and HER4. HER family members occur on the surfaces of many cell types and regulate cell division and proliferation, processes closely linked to both normal tissue growth and the abnormal growth seen in cancer.

A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by random genetic changes (somatic mutations) that make HER family receptor tyrosine kinases more active drivers of abnormal growth. About of 30 percent of nonsmall cell cancers (NSCLCs) and 90 percent of colon cancers are driven by small genetic changes in HER1, while 25 percent of breast cancers proceed from genetic changes that result in excessive amounts of HER2.

Mechanistically, HER proteins are transmembrane tyrosine kinase receptors. To drive life processes, signals must travel between cells, arrive at cell surfaces, and be passed on inside cells. When a signaling molecule like a growth factor docks into a specially shaped receptor protein on a cell’s outer surface, like a key into a lock, it changes shape of the receptor such that a biochemical message is passed on inside the cell to promote survival and growth.

In the case of a tyrosine kinase receptor, the docking of its signaling partner on the outside of the cell turns on its attached kinase inside the cell. Kinases partner with the molecule used as cellular energy currency, adenosine triphosphate (ATP), to attach a phosphate group to another molecule, which cells use like a switch to kick off chain reactions, some related to growth.

Dr. Zaidi and colleagues show that bisphosphonates themselves bind to the kinase domains of HER proteins, preventing the passing on of growth signals. For this reason, drugs that block the action of tyrosine kinases (inhibitors) like trastuzumab (Herceptin), erlotinib (Tarceva) and gefitinib (Iressa) have dramatically improved survival of cancer patients, but therapy for more than three years in a row invariably results in resistance.

By killing off cancer cells that specifically signal either through HER1 or HER 2 only, leading treatments create evolutionary pressure, and over time tumors come to be made up of more and more of cancer cells that have a second mutation that prevents binding of therapies to prevent growth. The current study suggests that bisphosphonates may block the function of HERs even when second mutations are present, and hence have the potential of treating cancers that have become resistant to primary therapy.

Detective Work
Having seen that some people taking bisphosphonates have lower incidence of several cancers, the study authors analyzed the genes that become more or less active when a patient takes these medications using the Connectivity Map (cmap). The well-known database, built by The Broad Institute at MIT, analyzes connections between drugs, diseases and genes, and in particular, identifies genes that become active or inactive when people are treated with a given class of drugs.

Once the team detected a digital cmap link between bisphosphonates and the HER receptor, they conducted experiments in cancer cell cultures and mice that confirmed the potential value of treating HER-driven cancers with bisphosphonates alone, and in combination with an approved tyrosine kinase inhibitor in Tarceva (iritinib). Giving mice bisphosphonates early on prevented HER-driven tumors from forming in the first place. Combining bisphosphonates with the tyrosine kinase inhibitor not only stopped tumor growth in mice, but reversed it. In contrast, mice with colon cancer cells that do not signal for growth using HER receptors remained insensitive to bisphosphonate action.

“While this finding is exciting, there is no business model for conducting the costly clinical trials that would be needed to repurpose bisphosphonates for cancer,” said Dr. Zaidi. “Pharmaceutical companies are unlikely to pay for research to develop generic drugs where there is no chance of patent protection or profit, so we will be looking for a non-traditional funding source, perhaps the federal government.”

About the Research Team
Authors on both PNAS papers, along with Dr. Zaidi, in the Departments of Medicine, Pediatrics, and Chemical and Structural Biology; and in the Tisch Cancer Institute with the Icahn School of Medicine at Mount Sinai; were Tony Yuen, Agnes Stachnik, Jameel Iqbal, Yogesh Gupta, Ping Lu, Graziana Colaianni, Yaoting Ji, Ling-Ling Zhu, Se-Min Kim, Jianhua Li, Peng Liu, Sudeh Izadmehr, Jaya Sangodkar, Shiraz Mujtaba, Solomon Epstein, Aneel Aggarwal, Maria New, Li Sun and Goutham Narla. Study authors also included Miriam Sgobba and Shozeb Haider in the School of Pharmacy at University College in London, Alberta Zallone of the Department of Histology at the University of Bari in Italy, and Zhuan Bian in the School of Stomatology at Wuhan University in China.

Mount Sinai authors only on the first paper, “Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer,” were Thomas Scherer, Matthew Galsky, Jorge Gomez, and Christoph Buettner. Mount Sinai authors only on the second paper, titled “Bisphosphonates inactivate human EGFRs to exert antitumor action,” were Jack Bailey, Yathin Latif, and Terry Davies.

The work was supported by grants from the National Institutes of Health (DK80459, AG40132, AG23176, AR06592, and AR06066), the Italian Space Agency, the National Science Foundation of China, the National Center for Advancing Translational Science through Mount Sinai School of Medicine’s Clinical and Translational Science Award, and a Howard Hughes Medical Institute Physician-Scientist Early Career Award (KL2TR000069).

About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community‐based facilities to tertiary and quaternary care.

The System includes approximately 6,600 primary and specialty care physicians, 12‐minority‐owned free‐standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.
For more information, visit http://www.mountsinai.org, or find Mount Sinai on Facebook, Twitter and YouTube.
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Old 12-02-2014, 01:10 PM   #2
thinkpositive
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Re: Simple cheap drugs already approved vs. osteoporosis may prevent, reverse her2+br

Thanks for posting this....very interesting
__________________
8/2013 Diagnosed IDC Left Breast ER-/PR-/HER2+ Stage 3C, DCIS ER+/PR+/HER2- Right Breast (54 yr)
8/2013 PET/CT scan shows mass in uterues and suprclavicular nodes
8/20/13 Begin 6 rounds TCH chemo, Perjeta added for rounds 4-6
9/2013 After 1st round of chemo, mass in neck and breast no longer able to feel
11/2013 Hysterectomy, mass from PET/CT scan not cancer (adenomylosis)
12/2013 Finished chemo
1/2014 Double mastectomy with chest expanders
1/2014 Pathology report from surgery and SNB show complete pathological response!
3/2014 Finish IMRT radiation
8/2014 Fat transfer to radiated breast
8/2014 Completed 1 yr of Herceptin
10/2014 exchange surgery expanders removed implants placed
6/2015 3D nipple and areola tattoos
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Old 12-03-2014, 05:48 AM   #3
Bunty
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Re: Simple cheap drugs already approved vs. osteoporosis may prevent, reverse her2+br

Very interesting indeed - I just had my first annual Aclasta infusion, so I hope there is definitely something in this research!
Thanks Lani - again!!
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dx Dec 2000 dcis 2.5cm clear sentinel node, ER/PR- Her-2+
lumpectomy, 6 cycles AC, 6 weeks rads
October 2007 three x 2.5cm lung mets. 8 months Taxol, started Herceptin and continue. Significant reduction in lung mets.
June 2011 3cm x 4cm liver tumour. Started Abraxane and continue with Herceptin.
November 2011. Finished with Abraxane, continue with just Herceptin. Liver tumour now reduced to 15mm x 12mm. Lung tumour now 10mm x 0.5mm
February 2012. Scans show everything stable, and brain scan clear.
July 2012. PET/CT scans show I'm in remission - no active cancer!
]Dec CT brain cllear, lungs stable, liver tumour has increased to 20mm. PET scans showed active liver met and active lung thinglet, and possible bone met.
Jan 2013 recommence Abraxane, continue with Herceptin.
June 2013 finish Cycle 6 Abraxane, continue with Herceptin. 30% reduction in liver tumour, everything stable.
December 2013. CA15-3 on rise.
February 2014. PET and CT scans show single liver tumour has increased to 35mm. No other activity.
March 2014. Planned for SBRT for liver met, but couldn't have treatment as tumour too close to bowel. Continue Herceptin.
April 2014. Surgeon advises that I am a good candidate for liver resection, so will have operation early May (after camping holiday). Tumour now 44mm x 29mm.
May 7, 2014. Two liver tumours surgically removed. Third of liver removed, and gall bladder. Am I NED?May 2014. Pathology of tumour shows it's now ER+ (95% staining).
June 2014. CA15-3 has decreased to 18 from a pre-surgery reading of 59!
June 2014. Started Femara, continue with Herceptin.
July 2014. Stop Femara due to severe Osteoporosis. Commence Tamoxifen, continue Herceptin. Waiting to hear if I can have Aclasta infusion.
August 2014. CA15-3 has decreased further to 12 - YAY!
October 2014. Aclasta infusion for Osteoporosis. November 2014, CA15-3 decreased to 11. Scans of liver all clear, something new showing up on lung, but just watching at the moment.
November 2015. Started SBRT on solitary lung met.
November 2015. Bone density scan showed very good improvement so back on Femara - yay!
December 2016. 6 treatments of SBRT radiation on lung. Seems to have had some effect.
June 2016. CA15-3 still stable and low at 9.
June 2016. Started subcutaneous Herceptin replacing infusion.
Jan 2017. LVEF dropped to 46%. Stopped Herceptin.
Feb 2017. Started ACE Inhibitor and BETA Blocker. Still off Herceptin.
Aug 2017. Two new mets - Portacaval lymph node and mediastinal lymph node.
Aug 2017. Blood tests show extremely elevated liver enzyme levels. Many tests to investigate.
Sept 2017. Portacaval lymph node blocking liver bile duct causing liver enzyme and Bilirubin problems.
Oct 2017. 8cm stent inserted into liver bile duct. Procedure caused pancreatitis, and hospitalised for 3 days. Liver enzymes improving rapidly.
Nov 2017. Commenced 4 weeks of radiation on Portacaval lymph node. 5 week break before chemo.
Jan 2018. CT scan. 11 new small liver mets, and new superclavical lymph node med.
Jan 2018. Start Kadcyla. CA15-3 426.
Apr 2018. First scans since starting Kadcyla. All tumours reducing. CA15-3 dropped to 30 from 426.
Dec 2019. Still on Kadcyla, but two small brain mets have been treated in the past month with SRS. CA15-3 stable for 12 months at 11.
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Old 12-03-2014, 11:05 AM   #4
lkc Gumby
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Re: Simple cheap drugs already approved vs. osteoporosis may prevent, reverse her2+br

yep, been on Zometa for 3 years and all's good.
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Linda

Dxed Stage IIIC May 05, 12 pos nodes
er/pr -neg,Her -pos
LVI
Right partial mast & partial axillary dissection-June14,2005
Right modified mast-no clear margins- June 30, 2005
DD AC x4
Taxotere X4 with Herceptin
Rads x 35( 5 fields )
Left prophylactive mast( atypia & hyperplasia found ),
put on Tamoxifen x 1 yr; D/ced due to endometrial thickening
bilateral recon (saline implants)May 06
Nipple recon July 06
metformin 2010
removal of implants due to severe encapsulation, insertion of gummies 2013
Reclast Q yr
NED!!!
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Old 12-11-2014, 02:10 PM   #5
Mtngrl
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Re: Simple cheap drugs already approved vs. osteoporosis may prevent, reverse her2+br

Wow. Fascinating.
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Amy
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4/19/11 Diagnosed invasive ductal carcinoma in left breast; 2.3 cm tumor, 1 axillary lymph node, weakly ER+, HER2+++
4/29/11 CT scan shows suspicious lesions on liver and lungs
5/17/11 liver biopsy
5/24/11 liver met confirmed--Stage IV at diagnosis
5/27/11 Begin weekly Taxol & Herceptin for 3 months (standard of care at the time of my DX)
7/18/11 Switch to weekly Abraxane & Herceptin due to Taxol allergy
8/29/11 CT scan shows no new lesions & old lesions shrinking
9/27/11 Finish Abraxane. Start Herceptin every 3 weeks. Begin taking Arimidex
10/17/11--Brain MRI--No Brain mets
12/5/11 PET scan--Almost NED
5/15/12 PET scan shows progression-breast/chest/spine (one vertebra)
5/22/12 Stop taking Arimidex; stay on Herceptin
6/11/12 Started Tykerb and Herceptin on clinical trial (w/no chemo)
9/24/12 CT scan--No new mets. Everything stable.
3/11/13 CT Scan--two small new possible mets and odd looking area in left lung getting larger.
4/2/13--Biopsy of suspicious area in lower left lung. Mets to lung confirmed.
4/30/13 Begin Kadcyla/TDM-1
8/16/13 PET scan "mixed," with some areas of increased uptake, but also some definite improvement, so I'll stay on TDM-1/Kadcyla.
11/11/13 Finally get hormone receptor results from lung biopsy of 4/2/13. My cancer is no longer ER positive.
11/13/13 PET scan mixed results again. We're calling it "stable." Problems breathing on exertion.
2/18/14 PET scan shows a new lesion and newly active lymph node in chest, other progression. Bye bye TDM-1.
2/28/14 Begin Herceptin/Perjeta every 3 weeks.
6/8/14 PET "mixed," with no new lesions, and everything but lower lungs improving. My breathing is better.
8/18/14 PET "mixed" again. Upper lungs & one spine met stable, lower lungs less FDG avid, original tumor more avid, one lymph node in mediastinum more avid.
9/1/14 Begin taking Xeloda one week on, one week off. Will also stay on Herceptin and Perjeta every three weeks.
12/11/14 PET Scan--no new lesions, and everything looks better than it did.
3/20/15 PET Scan--no new lesions, but lower lung lesions larger and a bit more avid.
4/13/15 Increasing Xeloda dose to 10 days on, one week off.
7/1/15 Scan "mixed" again, but suggests continuing progression. Stop Xeloda. Substitute Abraxane every 3 weeks starting 7/13.
10/28/15 PET scan shows dramatic improvement everywhere. All lesions except lower lungs have resolved; lower lungs noticeably improved.
12/18/15 Last Abraxane. Continue on Herceptin and Perjeta alone beginning 1/8/16.
1/27/16 PET scan shows cancer is stable.
5/11/16 PET scan shows uptake in some areas that were resolved on the last two scans.
6/3/16 Begin Kadcyla and Tykerb combination
6/5 - 6/23 Horrible diarrhea from K&T together. Got pneumonia.
7/15/16 Begin Kadcyla only every 3 weeks.
9/6/16 Begin radiation therapy on right lung lesion that caused the pneumonia.
10/3/16 Last of 12 radiation treatments to right lung.
11/4/16 Huffing and puffing, low O2, high heart rate, on tiniest bit of exertion. Diagnosed as radiation pneumonitis. Treated with Prednisone.
11/11/16 PET scan shows significant improvement to radiated part of right lung BUT a bunch of new lung lesions, and the bone met is getting worse.
11/22/16 Begin Eribulin and Herceptin. H every 3 weeks. E two weeks on, one week off.
3/6/17 Scan shows progression in lungs. Bone met a little better.
3/23/17 Lung biopsy. Tumor sampled is ER-, PR+ (5%), HER2+++. Getting Herceptin and Perjeta as a maintenance treatment.
5/31/17 Port placement
6/1/17 Start Navelbine & Tykerb
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Old 12-11-2014, 03:12 PM   #6
Carol Ann
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Re: Simple cheap drugs already approved vs. osteoporosis may prevent, reverse her2+br

YES! I have been taking Fosamax and my once told me when I started in April there were some early studies saying there might be some prevention of metastasis ... this adds to those he quoted then.

It's all good news, I'll take it!

Carol Ann
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July 24, 2013: "Infected" Right Nipple and benign cyst removed, pathology report revealed Paget's, DCIS, and ILC 1.25 cm, ER+/Pro+/HER2 equivocal, Grade 2 under benign cyst, previous diagnostic mammo/ultrasound said I was perfectly healthy in both breasts.

Aug 18, 2013: MRI report says Left breast is perfectly healthy "consistent with previous studies".

Sept 2013: I insist on a bilateral mastectomy anyway. Too nervewracking to let left breast remain with higher risk after 3 cancers in right, nipple in right is already gone anyhow.

Sept 18, 2013: Bilateral mastectomy, 11 right nodes removed, ALL negative BUT -- ER+/PRO+/HER2+ tumor, 1.0 cm, Grade 2 found in a piece of "grossly unremarkable" breast tissue from prophylactic mastectomy of left breast, no nodes removed.

Oct 25, 2013: 13 left side nodes removed, ALL negative, Stage 1 across the board, NO RADS needed, YAAAAY! Port also installed.

Nov 25, 2013 Begin 6 rounds TCH.

March 10, 2014 Just finished 6th and LAST Chemo today, YAAAAAY!

March 24, 2014 Echocardiogram to make sure I'm still good for Herceptin every 3 weeks.

March 31, 2014 Echo results NORMAL, first Herceptin all by itself. Now if only my eyes would stop streaming from the Taxotere ... :)

April 21, 2014 Started Arimidex and therapy for "mild" lymphedema in left hand and arm

May 2014 Therapy completed, I have sleeves and gloves for both arms, a Flexi touch lymph pump to hook up to for an hour every day, and I've become an arm bandaging expert. :)

June 2014 Begin Fosamax to prevent osteoporosis; bone scan revealed osteopenia

Nov 17, 2014 FINAL Herceptin!

Dec 4, 2014 My right thigh muscle has been extra achy for days ... I discover a blister rash cluster on the side of my right thigh while taking a shower. Port appointment cancelled until Dec 17, my doc is working me in tomorrow afternoon to see me and the rash. My muscle at least feels less achy.

Dec 5, 2014 Yep, I have shingles. Boo! I start acyclovir and also have a prescription for a painkiller just in case for over the weekend.

Dec 17, 2014 Port is OUT!

January 2016 Shingles again and this time it started where my left breast (where the hidden HER2+++ tumor was!) used to be. My onc nurse got me a same day appointment to see my doc when I called and told her I had a rash on the site. The antiviral meds are working once again, though, so that is good news. :)
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Old 12-12-2014, 08:09 PM   #7
KaiM
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Re: Simple cheap drugs already approved vs. osteoporosis may prevent, reverse her2+br

Very interesting! I have been on biophosphates (zoo meta and Xgeva) since my initial diagnosis three years ago and as Gumby said 'all is good'!
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9/11 - dx 3 mnths after giving birth to my 2nd child. (not a clogged milk duct) ER/PR- HER2+++
10/11 - Initially staged at 2b after unilateral mastectomy
11/11 - CT scan 4 weeks later found spots on bones and liver (crap!) Stage 4
12/11 - starting TCH
5/12 - STABLE. stoping TCH after 6 months and continuing Herceptin with Tykerb and Xgeva
8/12 - STABLE, but I'm calling it NED because all they see is bone scaring!
11/12 - STABLE
2/13 - STABLE
6/13 - STABLE
9/13 - STABLE
12/13 - STABLE
3/14 - STABLE
6/14 - STABLE
9/14 - STABLE
12/14 - STABLE
...Continue Herceptin and daily Tykerb and scans every 4 months
1/16 - STABLE
11/18 - Five level spinal fusion from collapsing vertebrae due to spinal Mets/radiation
12/19 - STABLE
Mom to Audrey (12 yrs) and Hudson (8)

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