Medical New target for treating pancreatic cancer identified

Wrichik Basu

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Interesting paper:

Chandrayee Ghosh et. al., Super-enhancers: novel target for pancreatic ductal adenocarcinoma
Abstract said:
Super-enhancers (SEs) are unique areas of the genome which drive high-level of transcription and play a pivotal role in the cell physiology. Previous studies have established several important genes in cancer as SE-driven oncogenes. It is likely that oncogenes may hack the resident tissue regenerative program and interfere with SE-driven repair networks, leading to the specific pancreatic ductal adenocarcinoma (PDAC) phenotype. Here, we used ChIP-Seq to identify the presence of SE in PDAC cell lines. Differential H3K27AC marks were identified at enhancer regions of genes including c-MYC, MED1, OCT-4, NANOG, and SOX2 that can act as SE in non-cancerous, cancerous and metastatic PDAC cell lines. GZ17-6.02 affects acetylation of the genes, reduces transcription of major transcription factors, sonic hedgehog pathway proteins, and stem cell markers. In accordance with the decrease in Oct-4 expression, ChIP-Seq revealed a significant decrease in the occupancy of OCT-4 in the entire genome after GZ17-6.02 treatment suggesting the possible inhibitory effect of GZ17-6.02 on PDAC. Hence, SE genes are associated with PDAC and targeting their regulation with GZ17-6.02 offers a novel approach for treatment.
I haven't yet read the whole paper (which is free-access), but I believe it is worth a read.
 

Ygggdrasil

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The drug discussed in the article is currently in Phase I clinical trials for treating a variety of cancers (https://clinicaltrials.gov/ct2/show/NCT03775525).

Genzada Pharmaceuticals USA Inc., a subsidiary of Ionics Life Sciences Limited (Genzada), announced today that the U.S. Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) application for a Phase 1 human clinical trial of the company’s flagship molecule GZ17-6.02 (6.02) for patients with advanced solid organ tumors or lymphoma.

“We are excited to bring 6.02 to the oncology community and we look forward to demonstrating its safety and efficacy as we move through the clinical trials process,” said Cameron E. West, MD, FAAD, chief operating officer of Genzada. “Based on numerous preclinical studies, we believe this therapeutic will be very well-tolerated and will achieve meaningful outcomes for cancer patients.”

6.02 has shown preclinical success in several therapeutic contexts, notably for pancreatic cancer and head and neck squamous cell carcinoma.
(source: https://www.businesswire.com/news/home/20181116005277/en/First-in-Human-Trial-Launched-Super-Enhancer-Inhibitor-GZ17-6.02)

The senior author of the paper in the OP consults for the company that is testing the drug in clinical trials.

Others are also looking at the involvement of super-enhancers in cancer (though there is currently some debate in the field about whether "super-enhancers" are any different than normal enhancers):
Experimental cancer treatments that harness souped-up segments of DNA called super-enhancers to activate genes are working their way to the clinic for the first time. But scientists are still debating how these elements work — and whether they represent a fundamentally new way of regulating genes.

Screening for a particular super-enhancer can identify people with acute myeloid leukaemia who might benefit from a drug called tamibarotene, suggest preliminary data presented by the drug’s maker, Syros Pharmaceuticals, on 2 December at a meeting of the American Society of Hematology in San Diego, California. And on 15 November, the company debuted data from another preliminary trial, in which patients with solid tumours were given a drug that targets a protein called CDK7. Laboratory tests have shown1 that inhibiting this protein can reduce activity of a super-enhancer that has been linked to some cancers.
(source: https://www.nature.com/articles/d41586-018-07602-8)
 

BWV

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Odds are its total crap. Phase I drugs with big claims are a dime a dozen

Same guy also makes this miracle herbal supplement cure

 

pinball1970

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Odds are its total crap. Phase I drugs with big claims are a dime a dozen

Same guy also makes this miracle herbal supplement cure

The web site for the herbal stuff looks very vague, no specific health benefit, no specific remedy or mechanism of action mentioned anywhere. Just years of research and health benefits.Vit C and garlic were mentioned and that is where I decided I had read enough.

That aside, the trial group criteria in the drug study makes grim reading to say the least.
 
M

member 664484

The web site for the herbal stuff looks very vague, no specific health benefit, no specific remedy or mechanism of action mentioned anywhere. Just years of research and health benefits.Vit C and garlic were mentioned and that is where I decided I had read enough.

That aside, the trial group criteria in the drug study makes grim reading to say the least.
Here are some facts. GZ17-6.02 has in vitro and in vivo data see the paper at link and is a novel approach to cancer which is supported by some of the leading scientific researchers in the field who are involved in the Phase 1 clinical trial, including Dr. Von Hoff who has been involved in many successful efforts to get NDA approvals on chemotherapies.

In the study, GZ17-5.0 is the Afaya Plus supplement that is sold by Hyatt Life Sciences. GZ17-S is a tea version that was never formally marketed. GZ17-5.0 is composed of 16 different compound molecules. In GZ17-6.02 they reduced this to the three that were felt to be the most relevant. I believe based on my experience with experimental drugs, that this reduces the complexity of the analysis required to obtain the New Investigational Drug (NDI) approval from the FDA. The more molecules, the harder it becomes to understand the mechanism of action.

By law, Hyatt Life Sciences cannot make any claims regarding whether a supplement can be used to treat a disease, especially cancer. That is why the site is vague in its claims. It has to be or they go to jail.

Fortunately for my wife, they decided to make a supplement first before the drug. My wife is stage IV pancreatic cancer. There is no FDA approved drug that can stop the cancer other than chemotherapy drugs and she is far enough along in the disease progression that she cannot take chemotherapy at the needed dosages to extend her life. The side effects are too debilitating. Unfortunately, while there are some novel experimental drugs and even some ones like GZ17-6.02 in clinical trial, they are not attainable for her because her ECOG is not good enough or they have not received their NDI and thus cannot be administered by any licensed physician without them losing their license. So you see having a supplement available that is essentially the same as the drug in clinical trial throws many patients such as my wife a life line.

While I am a biomedical engineer, I have consulted with a top scientist/drug researcher who also believes this drug should not be dismissed, just because it starts out in nature and has a supplement. 25% of prescription drugs start in nature.

So far, GZ17-5.0 ( Afaya Supplement), in conjunction with chemotherapies Gemzar and Abraxane is working. At a minimum, it has reduced the side effects of the chemotherapy, but more importantly there are physiological signs that she is improving
 

pinball1970

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Here are some facts. GZ17-6.02 has in vitro and in vivo data see the paper at link and is a novel approach to cancer which is supported by some of the leading scientific researchers in the field who are involved in the Phase 1 clinical trial, including Dr. Von Hoff who has been involved in many successful efforts to get NDA approvals on chemotherapies.

In the study, GZ17-5.0 is the Afaya Plus supplement that is sold by Hyatt Life Sciences. GZ17-S is a tea version that was never formally marketed. GZ17-5.0 is composed of 16 different compound molecules. In GZ17-6.02 they reduced this to the three that were felt to be the most relevant. I believe based on my experience with experimental drugs, that this reduces the complexity of the analysis required to obtain the New Investigational Drug (NDI) approval from the FDA. The more molecules, the harder it becomes to understand the mechanism of action.

By law, Hyatt Life Sciences cannot make any claims regarding whether a supplement can be used to treat a disease, especially cancer. That is why the site is vague in its claims. It has to be or they go to jail.

Fortunately for my wife, they decided to make a supplement first before the drug. My wife is stage IV pancreatic cancer. There is no FDA approved drug that can stop the cancer other than chemotherapy drugs and she is far enough along in the disease progression that she cannot take chemotherapy at the needed dosages to extend her life. The side effects are too debilitating. Unfortunately, while there are some novel experimental drugs and even some ones like GZ17-6.02 in clinical trial, they are not attainable for her because her ECOG is not good enough or they have not received their NDI and thus cannot be administered by any licensed physician without them losing their license. So you see having a supplement available that is essentially the same as the drug in clinical trial throws many patients such as my wife a life line.

While I am a biomedical engineer, I have consulted with a top scientist/drug researcher who also believes this drug should not be dismissed, just because it starts out in nature and has a supplement. 25% of prescription drugs start in nature.

So far, GZ17-5.0 ( Afaya Supplement), in conjunction with chemotherapies Gemzar and Abraxane is working. At a minimum, it has reduced the side effects of the chemotherapy, but more importantly there are physiological signs that she is improving
If it is helping and she is improving then great
 
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By law, Hyatt Life Sciences cannot make any claims regarding whether a supplement can be used to treat a disease, especially cancer. That is why the site is vague in its claims. It has to be or they go to jail.
The reason that they cannot legally make any claims is precisely because there is no reliable scientific evidence to support any such claims. It may very well turn out that it is effective, but as of now there simply is no evidence to show that.

The preliminary data is encouraging enough to warrant further testing, but as was mentioned above, the outcome of such further testing is not assured and usually even when a drug makes it through clinical trials the actual magnitude of any effect is substantially smaller than was indicated in initial tests.
 
M

member 664484

The reason that they cannot legally make any claims is precisely because there is no reliable scientific evidence to support any such claims. It may very well turn out that it is effective, but as of now there simply is no evidence to show that.

The preliminary data is encouraging enough to warrant further testing, but as was mentioned above, the outcome of such further testing is not assured and usually even when a drug makes it through clinical trials the actual magnitude of any effect is substantially smaller than was indicated in initial tests.
Disagree. There are published scientific peer reviewed papers that provide the scientific evidence of efficacy against various cancer cell lines, but these scientists at Genzada and University of Kansas are responsible researchers who will not make claims until the drugs mechanisms of action are fully understood. That doesn't mean that there is no reliable scientific evidence regarding efficacy in animal models. I do agree with you that usually the magnitude of the effect tends to be less in humans because after all it is plant based. Fortunately the MTD has yet to be reached in human testing so larger doses or cycles can be specified.

GZ17 is a novel approach to PDAC in a cancer where a tolerable treatment is urgently needed. Primarily, past and current research has emphasized immunotherapy, metabolic, chemotherapy, and combinations of these. Everything to date has failed to impress, unless you are lucky enough to be one of the 2-3% who has high micro-satellite instability and can qualify for Keytruda or you have a BRCA mutation.

After three years of PDAC research, I have found that the most promise is from targeting certain family of genes involved in apoptosis and up regulating or down regulating proteins during transcription and post transcription. There are only two potential molecules that do that- GZ17 and FL118. FL118 will not enter clinical trial until early 2020. To say "no reliable scientific evidence" exists should be challenged when such a claim is made. So I am challenging you to cite specifics rather than making sweeping judgement calls
 
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There are published scientific peer reviewed papers that provide the scientific evidence of efficacy against various cancer cell lines,
None of those papers demonstrate efficacy for any clinical indication.

That doesn't mean that there is no reliable scientific evidence regarding efficacy in animal models.
Animal models are not human trials. Many drugs are effective in animal models and not humans. Again, it is promising enough to warrant further investigation, but premature to assert clinical efficacy.

I do agree with you that usually the magnitude of the effect tends to be less in humans because after all it is plant based.
That has nothing to do with it. It is a purely statistical effect. Preliminary results almost always overestimate an effect, statistically speaking. This is due to the multiple comparisons effect, which plagues drug research.

So I am challenging you to cite specifics rather than making sweeping judgement calls
Um, no, that isn’t the way it works. You are the one making claims with no data to back it up. Experiments in vitro are not evidence of clinical efficacy, nor are experiments in animal models, nor are even phase 1 clinical trials. Phase 2 clinical trials occasionally demonstrate clinical efficacy, but usually a solid phase 3 clinical trial is required before efficacy is established.

In the absence of even a completed phase 1 clinical trial, let alone phase 2 or 3, an assertion of “no evidence” to assert any clinical claims is fully warranted. Your insistence to the contrary is reckless.
 
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berkeman

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Interesting, I did not know about that effect.
Yes, it is an important effect that is given relatively short shrift in typical statistics classes. Particle physicists, on the other hand, consider it so important that they have given it a “pet name”: the look elsewhere effect.

Here is an interesting paper that goes over the issue in quite a bit of detail

 
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