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Probably the most up to date definition of a Chk1 Inhibitor in this fine Publication and a must read especially “Emerging DNA Damage Signaling Inhibitors” as it means SRA737 as the only Chk1 in trials also with good efficacy and low toxicity and very good synergy and would have thought this is the best way to understand what SRA737 does without reading all other Publications and Sierra Oncology Presentions!

Plus again should fill your boots up with confidence that it will be taken forward, they are working it out I’m sure, also note the University of Texas MD Anderson involvement in this Publication!

ACKNOWLEDGMENT

We regret that not all published works on the topic could be cited in this review.
4Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
5Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

CORRESPONDING AUTHOR

Timothy A. Yap, MBBS, PhD, FRCP, Departments of Investigational Cancer Therapeutics (Phase I Program) and Thoracic/Head and Neck Medical Oncology, Institute for Applied Cancer Science, Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson

Full PDF!

The DNA Damaging Revolution: PARP Inhibitors and Beyond

https://ascopubs.org/doi/pdfdirect/10.1200/EDBK_238473

Is it me or is the article screaming try SRA737 in Combinations with PARP’s/PD-L1’s.

The main difficulty with combination therapy approaches is the development of overlapping toxicities, which can lead to subtherapeutic dosing. This was observed early on when both temozolomide and irinotecan were combined with several PARP inhibitors, and it continues to present a problem in developing new combination approaches.

“The question is, do we actually need rational combinations? My answer is yes,” Dr. Yap said. “Not all patients with BRCA1 and BRCA2 mutations will respond, and drug resistance is nearly inevitable.”

Dr. Yap said that although chemotherapy agents were the basis for much of the combination research so far, this is in the process of changing, with more focus on targeted agents such as VEGFR inhibitors, DDR-specific agents including ATR inhibitors and others, and immunotherapy combinations with PD-1/PD-L1 inhibitors.

Targeting DDR Pathways Remains Promising, Though Challenging

Other DDR Targets?

Aside from combination approaches, other research is ongoing into novel types of DNA damage response modulators. Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, spoke about some of these strategies, including targeting of ATR, WEE1, CHK1/2, and others.

“All of our drug development for these agents has been stuck in phase I and phase II development, with none of these agents entering in phase III at this point,” she said, noting the prominent issues with toxicity as the major stumbling block, as well as questions of who exactly would be the best patient populations for the various agents.

She spoke about a phase I trial of VX-970, an ATR inhibitor that showed promising preclinical activity. In spite of that early success, a study of 17 patients treated with the agent alone had only one response. It was very well tolerated as monotherapy, but significant toxicity emerged in a cohort that received VX-970 and carboplatin.

Downstream of ATM and ATR are CHK1 and CHK2. “These are important proteins when it comes to cell cycle regulation,” Dr. Azad said, although agents targeting them have been “inordinately difficult to develop.” Again, the major issue has been toxicity, even after 15 years of development in the clinic.

Still, some promising results have emerged recently. A phase II study published last year found good activity with prexasertib, a CHK1/2 inhibitor, in BRCA-wildtype recurrent high-grade serous ovarian cancer. There were eight responses in 28 patients, but there was a high rate of grade 4 neutropenia.

https://dailynews.ascopubs.org/do/10.1200/ADN.19.190298/full/

Word is getting around with this Research that’s being presented in Journals, have posted some off them, if your invested it should give you confidence that we are in a good place being invested!

Activating the Sting pathways maybe, immunotherapy companys are realizing the potential too combine their immuno-oncology drugs to increase the overall effects in all Cancer Indications this one is for Kidney Cancer!

SRA737 the only Chk1 Inhibitor available will activate the innate immune system via Sting pathway!

“Immunicum raised €34M on the Nasdaq Stockholm stock exchange last year to fund the development of its therapeutic pipeline. It has several programs testing its dendritic cell therapy including phase I trials in liver cancer and gastrointestinal stromal cancer. Furthermore, the company is also planning to test its therapies in combination with checkpoint inhibitors — drugs that stop tumors from evading the immune system.”

https://labiotech.eu/medical/immunicum-cancer-immunotherapy-cell/amp/?__twitter_impression=true

There is a lots going on between companys and latest research show exciting collaborations in combo’s niraparib, olaparib, pembrolizumab (Kedtruda) and over many indications of Cancer and also a lot being talked of PARP resistance and not working on its own but magical in combos the same as chk1, I think we will get our deal JV and milestones as too many validators of respectability from journals showing this is the next frontline potentially to regress certain Cancer mutations!

PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer

“Although olaparib monotherapy did not lead to T-cell recruitment or antitumor efficacy in vivo, these effects were reversed by the addition of PD-L1 blockade, and the efficacy of combined olaparib and immune-checkpoint blockade was abolished by STING or cGAS knockdown in tumor cells. These results further support the importance of intratumoral STING for the activity of PARP inhibitor–based treatment. Similar findings were observed with the CHK1 inhibitor prexasertib in SCLC models, suggesting that STING pathway activation may be a common mechanism among DNA damage–repair inhibitors.“

Disclosure of Potential Conflicts of Interest

“G.I. Shapiro reports receiving commercial research grants from Eli Lilly, Merck EMD-Serono, Merck & Co., and Sierra Oncol- ogy and is a consultant/advisory board member for Pfizer, Lilly, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, G1 Therapeutics, Roche, Merck EMD-Serono, Sierra Oncology“

https://cancerdiscovery.aacrjournals.org/content/candisc/9/6/722.full.pdf

In the absents of T.Sen full article of :-

Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer

This is a very good research article and lots of good passages for Chk1 Inhibitor research with immune checkpoint activation in here, also talks about the resistance on PARPi with Chk1 overcoming!

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

“To investigate the role of the DNA damage response in this process, they added specific inhibitors of ATM, ATR, or Chk1, and demonstrated that inhibition of any of these DNA damage checkpoint kinases could suppress PD-L1 upregulation. Next, the authors screened an siRNA library targeting DNA repair genes; they found that depletion of BRCA2, PALB2 and XRCC5 [encoding Ku80, involved in non-homologous end joining (NHEJ)] resulted in the largest increase in radiation- induced PD-L1 expression.”

“This highlights the importance of Chk1 activation via end resection as a key process in DSB-induced PD-L1 expression.”

“In BRCA2-mutated tumours, resistance to PARPi may occur via protection of the replication fork,12, 13 which is dependent on ATR activity.14 This ATR activity may lead to upregulation of PD-L1 and promote response to PD-1/PD-L1 blockade. In both scenarios of PARPi resistance in BRCA1/2-mutated tumours, the study by Sato et al. suggests that PD-1/PD-L1 inhibitors may be a useful therapeutic strategy (with or without concurrent DNA damaging agents) for tumours that have progressed on PARPi.”

“The work by Sato et al. highlights an important role for the DNA damage ATR/Chk1 checkpoint in regulating PD-L1 expression, thus linking DNA DSB signalling with regulation of the immune response. These observations have important clinical implications for therapy selection, particularly following progression on PARPi and other DNA damaging agents. They also have translational implications for the design of appropriate correlative studies in ongoing and future clinical trials of DNA damaging agents in combination with immunotherapy.”

https://www.nature.com/articles/s41416-018-0017-x.pdf

Some comments, passages and links about Triple Combo of SCLC SRA737+LDG anti-PD-L (Keytruda)

•10/10 (100%) regressions at the end of treatment (day 21)

• 8/10 (80%) sustained CRs / cures at day 60

“Sierra presented preclinical data in February providing evidence of biological synergy between SRA737 and immune checkpoint blockade, a breakthrough approach to cancer therapy that blocks the ability of the tumour cell to evade recognition and attack by the immune system. Sierra is investigating the potential of this combination approach, with further preclinical data expected to be presented in the first half of 2019 and is currently designing a clinical study.”

Summary:

Small cell lung cancer (SCLC) has demonstrated modest responses to immune-checkpoint blockade despite harboring a high mutational burden. In this issue, Sen and colleagues show remarkable synergy between inhibition of the DNA-damage response and the PD-1 axis, resulting in striking tumor regressions in SCLC mouse models.

At the 2019 American Association for Cancer Research

“preclinical data showing “profound synergy” for the triple combination of the CHK1 inhibitor SRA737 in combination with low-dose gemcitabine (LDG) and anti-PD-L1 immunotherapy in a mouse model of small cell lung cancer (SCLC)”

SCLC Accounts for 15% of all Lung Cancers cases in the US.

Dr Sen reports that this combination with immune checkpoint blockade and DNA damage repair completely regressed tumours in mouse models.

Sen and colleagues showed that treatment of human small cell lung cancer (SCLC) cell lines with inhibitors of the DNA damage response (DDR) components CHK1 and PARP resulted in increased expression of PD-L1 Further, inhibition of either CHK1 or PARP in immunocompetent genetically engineered mouse models (GEMM) of SCLC resulted in increased levels of cytosolic DNA, which activates the cGAS–STING innate immune signaling pathway to induce IRF3 activation and subsequently drive IFNß-mediated increases in PD-L1 expression and T-cell recruitment in SCLC GEMMs Consistent with these findings, treatment with a CHK1 or PARP inhibitor enhanced the efficacy of anti–PD-L1 therapy and resulted in SCLC tumor regression in vivo Together, these findings suggest that combined targeting of DDR proteins and immune checkpoint blockade is a potential therapeutic strategy for patients with SCLC.

Dr Triparna Sen - MD Anderson Cancer Center, Houston, Texas

https://ecancer.org/video/7768/efficacy-and-immune-correlates-of-the-sra737-plus-ldg-regimen-in-combination-with-anti-pd-l1-in-an-sclc-model.php

https://www.proactiveinvestors.co.uk/companies/news/217748/sareums-flagship-chk1-inhibitor-shows-serious-lung-cancer-potential-in-mouse-models-217748.html

“Small-cell lung cancer continues to be one of the most difficult-to-treat cancers where there is a significant need for transformative therapies”

Thanks Iamhappy and is certainly is a an eye opener with the presenter using the word cure with the triple combination treatment of SRA737 + Gemcitabine and Keytruda well worth a listen, can’t see a big player not coming in here!

http://media.rampard.com/sierraoncology/20190603/player.html

If you find any research Iamhappy can you post it please as have a busy day ahead! :/)

Tim would have been taking to the CRT fund and sounds positive that the milestones will be payed with a bigger company coming in to potentially too JV with Sierra to start the Combination trials, backing up the position with such promising data with the combo trials and Sierra has already tested SRA737 with Keytruda the best front line defense against NSCLC and also Sierra Management now taking directors buys so maybe something in the air!

This is the first time I’ve heard of this statement for Colorectal Cancer with the SRA737+LDG anti-PD-L1 combo as just thought the presentation slides showed the the significant regression in SCLC!

“At an analysts' meeting held during ASCO, Sierra presented similarly striking data with the SRA737+LDG anti-PD-L1 combination in a mouse model of colorectal cancer, with 80% regressions observed following three treatment cycles“

Old article not seen posted before but shows the potential in Cancer!

Establishing the role of tyrosine kinase 2 in cancer

The role of TYK2 in lung cancer is largely unknown. One possible involvement has been published by Gao et al., showing that mutations in the EGFR kinase domain lead to STAT3 activation in human lung adenocarcinomas. This effect was mainly mediated by IL-6 and hence also by TYK2 and JAK2 Thus, TYK2 could represent an attractive target for the development of novel therapies for lung cancer.

Concluding Remarks

TYK2 is a molecule with diverse functions in the regulation of the immune system. Its inhibition diversely affects the occurrence of different diseases such as EAE, allergic asthma, rheumatoid arthritis, systemic lupus erythematosus and cancer (Fig. 3). Thus, the development of therapeutics targeting TYK2 should be precisely correlated with the disease under consideration and possible interactions with other diseases should be carefully evaluated. So far, one specific TYK2 inhibitor has been tested in vitro, while TYK2 overexpressing mutants have been found among human tumor samples. Much developmental work needs to be done if a specific TYK2 inhibitor is planned for clinical use.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583936/pdf/onci-2-e22840.pdf

https://www.fiercepharma.com/pharma/amgen-maker-enbrel-to-pick-up-celgene-s-otezla-for-13-4b-will-ftc-hit-back

So there is good reason to push for other means of funding as I don’t think they would have a chance to get investment for (momelotinib).

SRA737 having an definite appeal for a combination therapy that targets one aspect of cancer cell death, Cancer can turn to a few ways to repair DNA so it’s the only CHK1 available to combination with and provides this role with as you say with efficacy and good safety but there are others DDR pathways for cancer cell deaths in PARP and WEE1 that are available and the ummuno-oncology drugs PD-L1 keytruda, so a CHK1 is very desirable in combo!

Merck and Astrazeneca Keytruda's Pembrolizumab was on the slide as the Immuno-oncology PD-L1, so I guess it could be!

The chk1 research come up in a new search 2019 so I think it’s the full text journal that has just been released!

https://cancerres.aacrjournals.org/content/canres/early/2017/05/10/0008-5472.CAN-16-3409.full.pdf

“Sareum programmes have progressed well since candidate nomination in September 2018, building on the compelling efficacy seen in disease models, the potential for once-daily oral dosing and good early safety profiles.”

And

“Data arising from some of this work are being prepared for submission to a peer-reviewed publication and a conference presentation.”

So herein will be data showing compelling efficacy and good early profiles!