Member Info for Fadec92

Touching the 200 day moving average now and that’s a big indicator would be great to be on the other side of it, the last time we went above it for a long period from a low point was in 2016 when it broke out and 5-6 bagged, we also left a decending recent negative area that’s why we went up on not much, also the 50 day moving average is getting close to crossing the 200 day moving average which is bullish!

Looks good, mm’s wanted to take up, let’s hope it does!

https://imgur.com/a/P7i8KAL

SRA737

Most notably, the establishment of the strong anti-tumor immune microenvironment observed when SRA737 is combined with low dose gemcitabine opens an opportunity for a highly efficacious and tolerable treatment regimen with a potentially distinct mechanism from that of standard chemotherapy or DDR inhibitors alone.

Further studies are warranted to determine if this approach would be beneficial with other chemotherapies, such as low dose platinum-based doublets, in combination with ICB and DDR inhibitors. While the RPP SCLC model used in the immune-competent animal experiments represents only part of the heterogeneity of SCLC, our previous work with olaparib and prexasertib in combination with anti-PD-L1 suggests that our observations are more broadly applicable to SCLC. As with many other cancer types, pre-clinical studies are limited to only a few immune-competent models of SCLC, consequently further validation of the combinations described here, will likely need to take place in a clinical setting.

I would agree with that RMM, initially I thought this patent application was for 1802 but with wording for Autoimmune, and with yourself finding the other TYK2 application which in it is mentioned T-ALL and Cancer genes BCL/MYC then it’s only logical to think that these 2 are the different TYK2 molecules!

More work required with this Patent Application (16/351620) a final rejection is not final, it means they have to pay more money and have 2 months to reply to the action!

https://imgur.com/a/RQ4g1GF

https://imgur.com/a/wcusEay

Thanks IAH, I think I know somebody that will we get messaging! :/)

https://adisinsight.springer.com/search

Anyone have access?

A good reason to get phase trials going with SRA737 and Niraparib!

The CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill carcinoma cells.

“PARP1 enhanced CHK1 inhibitor lethality, arguing that our cell death effect was due to on-target actions of the drugs. Thus, it is probable that SRA737 may have a different spectrum of off-target effectors compared to other CHK1 inhibitors that in our present studies are beneficial at enhancing the killing potential of SRA737 when combined with PARP1 inhibitors.

The drug combination utilized an ATM-AMPK/DNA damage signaling pathway to mediate many of its tumoricidal effects, and at the same time surprisingly also caused an endoplasmic reticulum stress response, i.e. eIF2a activation”

Conclusion

In conclusion, we have demonstrated that the novel CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill mam- mary and ovarian carcinoma cells. Our mechanistic and in vivo findings provide a strong foundation to perform phase I clinical trials in these malignancies combining SRA737 with the PARP1 inhibitor niraparib. Recently, within the past two months, Sierra Oncology has signed a clinical supply agreement with Janssen Research & Development, LLC. for access to TESARO’s ZEJULA® (niraparib). Sierra intends to evaluate its CHK1 inhibitor, SRA737, in combination with niraparib in the United Kingdom in patients with metastatic castration-resistant prostate cancer (mCRPC).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154848/pdf/kcbt-19-09-1472189.pdf

Rioconnection what’s your CRUK/ICR - genome etc angle?

There is no break contract, still in trials I think Thoth said have been extended, the clause of break of contract is if they stop developing SRA737 and will have to give it back, just an unwillingness to expand the trials with a combo PARPi, Anogenital without a partner of non diluted terms, they did talk of an interested big Immunotherapy company last summer we were thinking it was Merck because of the Pembrolizumab T.Sen mouse model combo with 737/Gem/Pd-1!

Clicked into other links with Nature.com by accident for JAK bits first bit is in there TP53, too much studying with different links open on same website!

JAK1/2 :- that’s why the JAK1 is very important in Cancer with TYK2 with IL-12/23 covering the balance the same as IL’s as JAK2 but TYK2 being known to be a safer way of inhibiting!

The evolution of immune evasion drivers

Tumour 2 harboured a truncal JAK2 frameshift mutation. In addition, a subclonal JAK2 splice-site mutation evolved in one clade and a frameshift mutation in region AE. Another subclone had acquired a JAK1 frameshift mutation but no evidence for biallelic inactivation was found. A subclonal frameshift mutation was present in HLA Data. Assessing the neoantigens binding to this HLA allotype revealed that this could lead to a 12% reduction in the number of neoantigens presented by these subclones. One clade in Tumour 2 furthermore acquired two disrupting mutations in B2M. Inspecting short read sequencing data confirmed that these were not located on the same allele but conferred biallelic inactivation which abrogates MHC Class I antigen presentation.

Discussion

The mutation load of individual tumour regions exceeded the number of truncal mutations by 73%, and still by 34% following subclonal deconvolution. Studies investigating mutation burden as immunotherapy biomarkers may hence benefit from MSeq to robustly and accurately estimate truncal mutation loads. Subclonal immune evasion drivers were identified in two of four cases. Mutations in the JAK1/2 and inactivation of B2M can confer resistance to checkpoint-inhibiting immunotherapy”

https://www.nature.com/articles/s41586-020-1969-6#ref-CR40

PDF :-

https://www.nature.com/articles/s41586-020-1969-6.pdf

Google TP53 (P53) gene mutations and CHK1 they come up in regular acedemic literature, 77%, CHK1 part of the ATR arm of single strand breaks with the other arm of DDR (DNA damage response being the ATM PARPS double strand breaks of BRAC1/2 gene mutations!

Article Press are relating too :-

Pan-cancer analysis of whole genomes

“We confirmed that many driver mutations that affect tumour-suppressor genes are two-hit inactivation events. For example, of the 954 tumours in the cohort with driver mutations in TP53, 736 (77%) had both alleles mutated, 96% of which (707 out of 736) combined a somatic point mutation that affected one allele with somatic deletion of the other allele. Overall, 17% of patients had rare germline protein-truncating variants (PTVs) in cancer-predisposition genes, DNA-damage response genes and somatic driver genes. Biallelic inactivation due to somatic alteration on top of a germline PTV was observed in 4.5% of patients overall, with 81% of these affecting known cancer-predisposition genes (such as BRCA1, BRCA2 and ATM).”

Also the strong link between MHC-1 class association of immunotherapy interventions with high being able to use PD-1 successfully and CLTA-4 and Low MHC-1 linked with evade mechanisms and the JAK/STAT pathways!

Immune exclusion and immune desert loss of MHC-1

https://imgur.com/a/n6GG6x9

CD8+ T-cell recognition thought MHC-1 B2M loss of JAK1/2 and T-cell ignorance and resistance too ICI Immune Checkpoint Inhibitors PD-1

https://imgur.com/a/rMAErW5

“High mutation and neoantigen loads are associated with immunotherapy benefit. Recent data suggested more specifically that a high burden of clonal mutations/neoantigens is important for immunotherapy success. Applying the NetMHC algorithm predicted strong class I MHC binding neoantigens per tumour. Between 215 and 926 of these were clonal. This is higher than clonal neoantigen loads reported for most lung cancers or melanomas. It is conceivable that this high clonal neoantigen burden explains the immunotherapy sensitivity of dMMR tumours”

Up regulation of MHC 1 :-

IL-12 is an essential cytokine for the differentiation to Th1 cells, which is required for the generation of type 1 cell-mediated immunity to cancer and infection. IFN-y produced by IL-12, then upregulates the expression of MHC class I and II molecules

Potent Antitumor Activity of IL-12 :-

The antitumor and antimetastatic activities of IL-12 have been extensively examined in a variety of murine tumor models including melanomas, mammary carcinomas, colon carcinoma, renal carcinoma, and sarcomas. For instance, administration of IL-12 into tumor-bearing mice can delay, reduce, and, in some cases, completely inhibit tumor development with significant therapeutic efficacy in many solid tumors as well as hematological leukemias and lymphomas.

Previous IL-12 inhibitors :-

In clinical trials, however, the therapeutic effect has been limited by low efficacy and systemic toxicities such as splenomegaly, leucopenia, and gastrointestinal toxicity. Although the reasons for the limited clinical efficacy of IL-12 in cancer patients remain incompletely understood.

The Balance (IL-12 - IL23)

Promotion of IL-23-Mediated Protumor Immune Responses by STAT3 while Inhibiting IL-12-Dependent Antitumor Immune Responses

Interactions between tumor and immune cells either enhance or inhibit cancer progression. STAT3 signaling within the tumor microenvironment was recently elucidated to induce a protumor cytokine, IL-23, while inhibiting a central antitumor cytokine, IL-12, thereby shifting the balance of tumor immunity toward tumorigenesis.

https://www.hindawi.com/journals/jir/2010/832454/

The balance between tumor-promoting inflammation and anticancer immunity in the TME is governed by pro-inflammatory and effector cytokines. Depending on the context and duration of activity, a single cytokine may exert anti or pro-tumorigenic activities.

Tyrosine kinase 2 (TYK2) propagates the signals of cytokines that shape the TME.

Type I and type II interferons (IFNs) are pivotal in anticancer immunity. TYK2 is central for the response to type I IFN and for the production of type II IFN as well as for the response to the IL-12 and IL-10 family of cytokines, which control immunity and inflammation.

TYK2 is responsible for tipping the balance between tumor-restrictive and tumor-promoting functions.

Regulation of Antitumor Immune Responses by the IL-12 Family Cytokines, IL-12, IL-23, and IL-27

1. Cancer immunotherapy has the potential of being the most tumor-specific treatment that can be devised.

2. More recently, several exciting cytokines have been characterized that have considerable promise for future cancer immunotherapy.

3. The identification of new cytokines will open up a novel avenue to develop the cancer immunotherapy.

4. Among them, the IL-12 family cytokines have quite unique properties that they are heterodimeric cytokines and produced by antigen-presenting cells such as macrophages and DCs, and play critical roles in the regulation of helper T differentiation.

5. IL-12 is one of the most powerful antitumor cytokine, accumulating evidence revealed that the individual members of the IL-12 family play distinct roles in the regulation of antitumor immune responses.

Recently, substantial numbers of evidence indicate that immune system also promotes the tumorigenesis, invasion, propagation, and metastasis of tumors. Moreover, infiltration of effector cells such as CTLs in tumors generally results in good prognosis, while infiltration of macrophages often leads to bad prognosis.

More recently, the molecular mechanism whereby the inflammation regulates the antitumor immune responses has been elucidated.

IL12 - IL23 Balance :-

In many tumors, signal transducers and activator of transcription (STAT)3 are activated, and thereby IL-12 production is inhibited, and antitumor immune surveillance is suppressed.

On the contrary, the production of IL-23, which plays critical roles in expansion and maintenance of Th17 cells producing inflammatory IL-17, is augmented through STAT3 activation, resulting in inflammation, which is advantageous in the promotion of tumorigenesis.

Same interferon IFN-? and interleukin receptors IL-12 and IL-23, in SDC-1802 Tim talks of redressing the balance between these two, it’s definitely to do with TYK2 and Inflammation immune response with both being deficient/LOF (Loss of Function) it looks as if the Janus Kinase family is responsible for a huge range of diseases, I suspect that a lot more of TYK2/JAK inhibiting molecules will follow in the clinical in the future!

Clinical Study linking DDR with ICB and applicable DDR Genome Publications!

Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1
Blockade in Advanced Urothelial Cancers

“Other non-neoantigen– and/or ML-based mechanisms have been postulated to account for the additional influence of DDR
alterations on ICB treatment outcome.

For example, the stimulator of interferon genes (STING) pathway was initially described
as a host response to viral infection and potential etiology for autoimmune diseases.

The STING pathway induces innate host response in preclinical cancer models and is activated upon contact with cytosolic DNA fragments, which culminate in a type 1 interferon response.

Accumulation of cytosolic DNA fragments that arise from defective DDR mechanisms provides triggers to prime the STING pathway for activation In a PD-1/PD-L1 blockade-resistant mouse model, exposure to synthetic DNA fragments leads to STING-dependent antitumor activity in combination with anti-PD-1, which further supports this hypothesis but awaits confirmation and replication in a clinical setting.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366295/pdf/JCO.2017.75.7740.pdf

DNA damage response as biomarkers informing a precision medicine approach to bladder cancer: what are the next steps

https://www.tandfonline.com/doi/pdf/10.1080/23808993.2019.1539621?needAccess=true

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961503/pdf/nihms962902.pdf

A little more incite into the various Tyk2 and Design!

JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

TYK2-selective inhibitors have been developed with the goal of blocking signaling downstream of the cytokines IL-6, IL-12, and IL-23, all of which are implicated in the pathogenesis of various autoimmune diseases. Investigational TYK2 inhibitors have shown exciting preclinical efficacy in models of psoriasis, lupus, and inflammatory bowel disease.

BMS986165 is a TYK2 inhibitor that was discovered using a phenotypic screen of
kinase inhibitors to identify ligands of the TYK2 pseudokinase domain. The pseudokinase domain was then targeted based on crystallographic structural information, resulting in pathogenesis of various autoimmune diseases.

BMS986165 is a TYK2 inhibitor that was discovered using a phenotypic screen of
allosteric inhibition and IBD, and a phase 2 trial is currently ongoing for the treatment of psoriasis 181 (NCT02931838).

BMS986165 ameliorates disease in preclinical models of SLE developed using structure-based design and are being tested in preclinical models of SLE and IBD and a phase 2 trial is currently ongoing for the treatment of psoriasis (NCT02931838).

Other TYK2 inhibitors, such as NDI-031232 and NDI-031407, were developed using structure-based design and are being tested in preclinical models.

Finally, several new inhibitors in phase 1 trials inhibit both JAK1 and TYK2. PF-06700841 was developed using a structurally enabled program in combination with high-throughput screening, and is being tested in psoriasis, and alopecia areata, with plans for a trial in IBD. 183 (NCT02969018, 02974868, 02958865).

SAR-20347 was discovered using high- throughput computational screening followed by secondary screening against a panel of 291 kinases, and is effective in mouse models of inflammatory skin disease.

Given differences between in vitro and in vivo selectivity of other jakinibs, this and other trials will determine whether TYK2-blockers are selective in clinical practice, and how selectivity might affect outcomes.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168198/pdf/nihms-989067.pdf

Institute Cancer Research thinks that the JAK1/2 STAT Pathways are involved with Signaling for Resistance to the Commercial Successful Immune Checkpoint Inhibitors ie Keytruda/Opdivo/Yervoy!

Cancers engaged in evolutionary arms race with immune system

Mutations to evade immune attack

Importantly, the two stomach and gullet tumours with the highest level of infiltration from immune cells had each developed several mutations that allowed them to evade immune attack.

These mutations occurred in genes called B2M, HLA and JAK1/2, which normally help immune cells to recognise and attack cancer cells. When the genes fail to function as normal, the immune system is unable to spot cancer cells despite their large numbers of mutations.

https://www.icr.ac.uk/news-archive/cancers-engaged-in-evolutionary-arms-race-with-immune-system

An intriguing pre-clinical observation in an immune-competent melanoma model is that acquired resistance to ICI blockade could be overcome by inhibiting JAK1/JAK2 signalling, suggesting that JAK/STAT signalling may have a more complex role in mediating response and resistance to ICI (Benci et al, 2016). Importantly, the impact of systemic JAK1/2 inhibition with a small molecule inhibitor (e.g., ruxolitinib) almost certainly differs from tumour-specific loss of functional JAK1 and/or JAK2 signalling. Moreover, ICI-resistant cells were derived using anti-CTLA-4 antibody treatment, which promotes Treg depletion (Simpson et al, 2013), a property yet to be demonstrated for human anti-CTLA-4 antibodies (e.g., ipilimumab). In light of reports of acquired resistance to cancer immunotherapy through immunoediting (Takeda et al, 2017) or acquired resistance via induction of a multigenic resistance programme (Benci et al, 2016), further studies will be required to evaluate the impact of interferon signalling as a driver of resistance to ICI therapy.

https://www.nature.com/articles/bjc2017434

https://www.nature.com/articles/bjc2017434.pdf

Mechanisms of resistance to immune checkpoint inhibitors

Monoclonal antibodies targeting co-inhibitory immune check- points (e.g., PD-1 and CTLA-4) have demonstrated clinical activity in several malignances, including melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma, and have changed the practice of medical oncology (Pardoll, 2012; Topalian et al, 2015; Sharma et al, 2017). Immune checkpoint inhibitor therapy has been particularly successful in melanoma, for which approved treatments now include anti-PD-1 (nivolumab and pembrolizu- mab), anti-CTLA-4 (ipilimumab), and combination anti-PD-1/ CTLA-4 regimens (nivolumab–ipilimumab.

Mutations in immune effector signalling pathways are capable of nullifying the impact of tumour-specific T cells. Whole exome sequencing of tumours from patients that developed resistance following initial clinical response to PD-1 blockade revealed mutations in Janus kinases 1 and 2 (JAK1/JAK2) (Zaretsky et al, 2016).

These mutations were detected in association with deletion of the wild-type allele resulting in total loss-of-function and loss of interferon responsiveness. This study also described a truncating mutation in B2M, the loss of which resulted in impaired cell surface expression of MHC class I, and defective antigen presentation. The frequency of such mutations appears low based on limited studies to date, but more widespread sequencing may identify additional mutations that lead to innate and/or acquired resistance to ICI therapy (Zaretsky et al, 2016; Shin et al, 2017). Consistent with these reports of loss-of-function mutations in JAK1/2 as an innate and acquired resistance mechanism, in vivo CRISPR screening using a mouse model of melanoma demonstrated that deletion of IFN? receptors (Ifrngr1 and Ifngr2) and JAK/STAT pathway components (Jak1, Jak2, and Stat1) resulted in resistance to PD-1 blockade (Manguso et al, 2017).