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The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cell Biology, Drug Development Process, Drug Discovery Chemistry, Genomic Expression, Loss of function gene, Metabolomics, Pharmaceutical Drug Discovery, tagged AAAS, anti-cancer therapy, Cancer - General, Cancer research, cancer resistance, chemoresistance, PROTAC, Proteasome, Proteolysis on October 11, 2022| Leave a Comment »

The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells

Reporter: Stephen J. Williams, PhD.

Below is one of the first reports  on the potential mechanisms of intrinsic and acquired resistance to PROTAC therapy in cancer cells.

SOURCE

https://www.science.org/doi/10.1126/scisignal.abn2707

ALISON M. KURIMCHAK HTTPS://ORCID.ORG/0000-0003-2608-0128CARLOS HERRERA-MONTÁVEZSARA MONTSERRAT-SANGRÀDANIELA ARAIZA-OLIVERA HTTPS://ORCID.ORG/0000-0002-8207-9765JIANPING HU HTTPS://ORCID.ORG/0000-0002-6000-4922RYAN NEUMANN-DOMERMATHEW KURUVILLAALFONSO BELLACOSA HTTPS://ORCID.ORG/0000-0001-6278-6801JOSEPH R. TESTAJIAN JIN HTTPS://ORCID.ORG/0000-0002-2387-3862 AND JAMES S. DUNCAN 

Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1 (which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRAS^G12C synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

INTRODUCTION

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary new class of drugs that use cancer cells’ own protein destruction machinery to selectively degrade essential tumor drivers (1). PROTACs are small molecules with two functional ends, wherein one end binds to the protein of interest, whereas the other binds to an E3 ubiquitin ligase (2, 3), bringing the ubiquitin ligase to the target protein, leading to its ubiquitination and subsequent degradation by the proteasome. PROTACs have enabled the development of drugs against previously “undruggable” targets and require neither catalytic activity nor high-affinity target binding to achieve target degradation (4). In addition, low doses of PROTACs can be highly effective at inducing degradation, which can reduce off-target toxicity associated with high dosing of traditional inhibitors (3). PROTACs have been developed for a variety of cancer targets, including oncogenic kinases (5), epigenetic proteins (6), and, recently, KRAS^G12C proteins (7). PROTACs targeting the androgen receptor or estrogen receptor are avidly being evaluated in clinical trials for prostate cancer (NCT03888612) or breast cancer (NCT04072952), respectively.

However, PROTACs may not escape the overwhelming challenge of drug resistance that befalls so many cancer therapies (8). Resistance to PROTACs in cultured cells has been shown to involve genomic alterations in their E3 ligase targets, such as decreased expression of Cereblon (CRBN), Von Hippel Lindau (VHL), or Cullin2 (CUL2) (9–11). Up-regulation of the drug efflux pump encoded by ABCB1—MDR1 (multidrug resistance 1), a member of the superfamily of adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporters—has been shown to convey drug resistance to many anticancer drugs, including chemotherapy agents, kinase inhibitors, and other targeted agents (12). Recently, PROTACs were shown to be substrates for MDR1 (10, 13), suggesting that drug efflux represents a potential limitation for degrader therapies. Here, using degraders (PROTACs) against bromodomain and extraterminal (BET) bromodomain (BBD) proteins and cyclin-dependent kinase 9 (CDK9) as a proof of concept, we applied proteomics to define acquired resistance mechanisms to PROTAC therapies in cancer cells after chronic exposure. Our study reveals a role for the drug efflux pump MDR1 in both acquired and intrinsic resistance to protein degraders in cancer cells and supports combination therapies involving PROTACs and MDR1 inhibitors to achieve durable protein degradation and therapeutic responses.

Fig. 1. Proteomic characterization of degrader-resistant cancer cell lines.
(A) Workflow for identifying protein targets up-regulated in degrader-resistant cancer cells. Single-run proteome analysis was performed, and changes in protein levels among parent and resistant cells were determined by LFQ. m/z, mass/charge ratio. (B and C) Cell viability assessed by CellTiter-Glo in parental and dBET6- or Thal SNS 032–resistant A1847 cells treated with increasing doses of dBET6 (B) or Thal SNS 032 (C) for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. Growth inhibitory 50% (GI50) values were determined using Prism software. (D to G) Immunoblotting for degrader targets and downstream signaling in parental A1847 cells and their derivative dBET6-R or Thal-R cells treated with increasing doses of dBET6 or Thal SNS 032 for 4 hours. The dBET6-R and Thal-R cells were continuously cultured in 500 nM PROTAC. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values, quantitating either (E) the dose of dBET6 that reduces BRD2, BRD3, or BRD4 or (G) the dose of Thal SNS 032 that reduces CDK9 protein levels 50% of the DMSO control treatment, were determined with Prism software. Pol II, polymerase II. (H to K) Volcano plot of proteins with increased or reduced abundance in dBET6-R (H) or Thal-R (I) A1847 cells relative to parental cells. Differences in protein log2 LFQ intensities among degrader-resistant and parental cells were determined by paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software. The top 10 up-regulated proteins in each are shown in (J) and (K), respectively. FC, fold change. (L and M) ABCB1 log2 LFQ values in dBET6-R cells from (H) and Thal-R cells from (I) compared with those in parental A1847 cells. Data are presented as means ± SD from three independent assays. By paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software, ***P ≤ 0.001. (N) Cell viability assessed by CellTiter-Glo in parental and MZ1-resistant SUM159 cells treated with increasing doses of MZ1 for 5 days. Data were analyzed as % of DMSO control, presented as means of three independent assays. GI50 values were determined using Prism software. (O and P) Immunoblotting for degrader targets and downstream signaling in parental or MZ1-R SUM159 cells treated with increasing doses of MZ1 for 24 hours. The MZ1-R cells were continuously cultured in 500 nM MZ1. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values were determined in Prism software. (Q and R) Top 10 up-regulated proteins (Q) and ABCB1 log2 LFQ values (R) in MZ1-R cells relative to parental SUM159 cells

Fig. 2. Chronic exposure to degraders induces MDR1 expression and drug efflux activity.
(A) ABCB1 mRNA levels in parental and degrader-resistant cell lines as determined by qRT-PCR. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (B) Immunoblot analysis of MDR1 protein levels in parental and degrader-resistant cell lines. Blots are representative of three independent experiments. (C to E) Immunofluorescence (“IF”) microscopy of MDR1 protein levels in A1847 dBET6-R (C), SUM159 MZ1-R (D), and Thal-R A1847 cells (E) relative to parental cells. Nuclear staining by DAPI. Images are representative of three independent experiments. Scale bars, 100 μm. (F) Drug efflux activity in A1847 dBET6-R, SUM159 MZ1-R, and Thal-R A1847 cells relative to parental cells (Par.) using rhodamine 123 efflux assays. Bars are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (G) Intracellular dBET6 levels in parental or dBET-R A1847 cells transfected with a CRBN sensor and treated with increasing concentrations of dBET6. Intracellular dBET6 levels measured using the CRBN NanoBRET target engagement assay. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 by Student’s t test. (H and I) FISH analysis of representative drug-sensitive parental and drug-resistant A1847 (H) and SUM159 (I) cells using ABCB1 and control XCE 7 centromere probes. Images of interphase nuclei were captured with a Metasystems Metafer microscope workstation, and the raw images were extracted and processed to depict ABCB1 signals in magenta, centromere 7 signals in cyan, and DAPI-stained nuclei in blue. (J and K) CpG methylation status of the ABCB1 downstream promoter (coordinates: chr7.87,600,166-87,601,336) by bisulfite amplicon sequencing in parent and degrader-resistant A1847 (J) and SUM159 (K) cells. Images depict the averaged percentage of methylation for each region of the promoter, where methylation status is depicted by color as follows: red, methylated; blue, unmethylated. Schematic of the ABCB1 gene with the location of individual CpG sites is shown. Graphs are representative of three independent experiments. (L and M) Immunoblot analysis of MDR1 protein levels after short-term exposure [for hours (h) or days (d) as indicated] to BET protein degraders dBET6 or MZ1 (100 nM) in A1847 (L) and SUM159 (M) cells, respectively. Blots are representative of three independent experiments. (N to P) Immunoblot analysis of MDR1 protein levels in A1847 and SUM159 cells after long-term exposure (7 to 30 days) to BET protein degraders dBET6 (N), Thal SNS 032 (O), or MZ1 (P), each at 500 nM. Blots are representative of three independent experiments. (Q and R) Immunoblot analysis of MDR1 protein levels in degrader-resistant A1847 (Q) and SUM159 (R) cells after PROTAC removal for 2 or 7 days. Blots are representative of three independent experiments.

 

Fig. 3. Blockade of MDR1 activity resensitizes degrader-resistant cells to PROTACs.
(A and B) Cell viability by CellTiter-Glo assay in parental and degrader-resistant A1847 (A) and SUM159 (B) cells transfected with control siRNA or siRNAs targeting ABCB1 and cultured for 120 hours. Data were analyzed as % of control, presented as means ± SD of three independent assays. ***P ≤ 0.001 by Student’s t test. (C and D) Immunoblot analysis of degrader targets after ABCB1 knockdown in parental and degrader-resistant A1847 (C) and SUM159 (D) cells. Blots are representative, and densitometric analyses using ImageJ are means ± SD of three blots, each normalized to the loading control, GAPDH. (E) Drug efflux activity, using the rhodamine 123 efflux assay, in degrader-resistant cells after MDR1 inhibition by tariquidar (0.1 μM). Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (F to H) Cell viability by CellTiter-Glo assay in parental and dBET6-R (F) or Thal-R (G) A1847 cells or MZ1-R SUM159 cells (H) treated with increasing concentrations of tariquidar. Data are % of DMSO control, presented as means ± SD of three independent assays. GI50 value determined with Prism software. (I to K) Immunoblot analysis of degrader targets after MDR1 inhibition (tariquidar, 0.1 μM for 24 hours) in parental and degrader-resistant A1847 cells (I and J) and SUM159 cells (K). Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. (L and M) A 14-day colony formation assessed by crystal violet staining of (L) A1847 cells or (M) SUM159 cells treated with degrader (0.1 μM; dBET6 or MZ1, respectively) and MDR1 inhibitor tariquidar (0.1 μM). Images are representative of three biological replicates. (N) Immunoblotting for MDR1 in SUM159 cells stably expressing FLAG-MDR1 after selection with hygromycin. (O) Long-term 14-day colony formation assay of SUM159 cells expressing FLAG-MDR1 that were treated with DMSO, MZ1 (0.1 μM), or MZ1 and tariquidar (0.1 μM) for 14 days, assessed by crystal violet staining. Representative images of three biological replicates are shown. (P and Q) RT-PCR (P) and immunoblot (Q) analysis of ABCB1 mRNA and MDR1 protein levels, respectively, in parental or MZ1-R HCT116, OVCAR3, and MOLT4 cells.

 

Fig. 4. Overexpression of MDR1 conveys intrinsic resistance to degrader therapies in cancer cells.
(A) Frequency of ABCB1 mRNA overexpression in a panel of cancer cell lines, obtained from cBioPortal for Cancer Genomics using Z-score values of >1.2 for ABCB1 mRNA levels (30). (B) Immunoblot for MDR1 protein levels in a panel of 10 cancer cell lines. Blots are representative of three independent experiments. (C) Cell viability by CellTiter-Glo assay in cancer cell lines expressing high or low MDR1 protein levels and treated with Thal SNS 032 for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (D to F) Immunoblot analysis of CDK9 in MDR1-low (D) or MDR1-high (E) cell lines after Thal SNS 032 treatment for 4 hours. Blots are representative, and densitometric analyses using ImageJ are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (G and H) Immunoblotting of control and MDR1-knockdown DLD-1 cells treated for 4 hours with increasing concentrations of Thal SNS 032 [indicated in (H)]. Blots are representative, and densitometric analysis data are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (I) Drug efflux activity using rhodamine 123 efflux assays in DLD-1 cells treated with DMSO or 0.1 μM tariquidar. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (J) Intracellular Thal SNS 032 levels, using the CRBN NanoBRET target engagement assay, in MDR1-overexpressing DLD-1 cells treated with DMSO or 0.1 μM tariquidar and increasing doses of Thal SNS 032. Data are % of DMSO control, presented as means ± SD of three independent assays. **P ≤ 0.01 and ***P ≤ 0.001 by Student’s t test. (K to N) Immunoblotting in DLD-1 cells treated with increasing doses of Thal SNS 032 (K and L) or dBET6 (M and N) alone or with tariquidar (0.1 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of Thal SNS 032 for CDK9 reduction (L) or of dBET6 for BRD4 reduction (N) determined with Prism. (O to T) Bliss synergy scores based on cell viability by CellTiter-Glo assay, colony formation, and immunoblotting in DLD-1 cells treated with the indicated doses of Thal SNS 032 (O to Q) or dBET6 (R to T) alone or with tariquidar. Cells were treated for 14 days for colony formation assays and 24 hours for immunoblotting.

 

Fig. 5. Repurposing dual kinase/MDR1 inhibitors to overcome degrader resistance in cancer cells.
(A and B) Drug efflux activity by rhodamine 123 efflux assays in degrader-resistant [dBET-R (A) or Thal-R (B)] A1847 cells after treatment with tariquidar, RAD001, or lapatinib (each 2 μM). Data are means ± SD of three independent experiments. *P ≤ 0.05 by Student’s t test. (C and D) CellTiter-Glo assay for the cell viability of parental, dBET6-R, or Thal-R A1847 cells treated with increasing concentrations of RAD001 (C) or lapatinib (D). Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (E to I) Immunoblot analysis of degrader targets in parental (E), dBET6-R (F and G), and Thal-R (H and I) A1847 cells treated with increasing concentrations of RAD001 or lapatinib for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of dBET6 for BRD4 reduction (G) or of Thal SNS 032 for CDK9 reduction (I) determined with Prism. (J) Immunoblotting for cleaved PARP in dBET6-R or Thal-R A1847 cells treated with RAD001, lapatinib, or tariquidar (each 2 μM) for 24 hours. Blots are representative of three independent blots. (K to N) Immunoblotting for BRD4 in DLD-1 cells treated with increasing doses of dBET6 alone or in combination with either RAD001 or lapatinib [each 2 μM (K and L)] or KU-0063794 or afatinib [each 2 μM (M and N)] for 4 hours. Blots are representative of three independent experiments and, in (L), are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for BRD4 reduction (L) determined in Prism. (O) Colony formation by DLD-1 cells treated with DMSO, dBET6 (0.1 μM), lapatinib (2 μM), afatinib (2 μM), RAD001 (2 μM), KU-0063794 (2 μM), or the combination of inhibitor and dBET6 for 14 days. Images representative of three independent assays. (P and Q) Immunoblotting for CDK9 in DLD-1 cells treated with increasing doses of Thal SNS 032 and/or RAD001 (2 μM) or lapatinib (2 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for CDK9 reduction determined with Prism (Q). (R) Colony formation in DLD-1 cells treated with DMSO, Thal SNS 032 (0.5 μM), lapatinib (2 μM), and/or RAD001 (2 μM) as indicated for 14 days.

 

Fig. 6. Combining MEK1/2 degraders with lapatinib synergistically kills MDR1-overexpressing KRAS-mutant CRC cells and tumors.
(A and B) ABCB1 expression in KRAS-mutant CRC cell lines from cBioPortal (30) (A) and MDR1 abundance in select KRAS-mutant CRC cell lines (B). (C) Cell viability assessed by CellTiter-Glo in CRC cells treated with increasing doses of MS432 for 5 days, analyzed as % of DMSO control. GI50 value determined with Prism software. (D) Colony formation by CRC cells 14 days after treatment with 1 μM MS432. (E) MEK1/2 protein levels assessed by immunoblot in CRC lines SKCO1 (low MDR1) or LS513 (high MDR1) treated with increasing doses of MS432 for 4 hours. (F) Rhodamine 123 efflux in LS513 cells treated with DMSO, 2 μM tariquidar, or 2 μM lapatinib. (G and H) Immunoblotting analysis in LS513 cells treated with increasing doses of MS432 alone or in combination with tariquidar (0.1 μM) or lapatinib (5 μM) for 24 hours. DC50 value for MEK1 levels determined with Prism. (I) Immunoblotting in LS513 cells treated with DMSO, PD0325901 (0.01 μM), lapatinib (5 μM), or the combination for 48 hours. (J and K) Immunoblotting in LS513 cells treated either with DMSO, MS432 (1 μM), tariquidar (0.1 μM) (J), or lapatinib (5 μM) (K), alone or in combination. (L) Bliss synergy scores determined from cell viability assays (CellTiter-Glo) in LS513 cells treated with increasing concentrations of MS432, lapatinib, or the combination. (M and N) Colony formation by LS513 cells (M) and others (N) treated with DMSO, lapatinib (2 μM), MS432 (1 μM), or the combination for 14 days. (O and P) Immunoblotting in LS513 cells treated with increasing doses of MS934 alone (O) or combined with lapatinib (5 μM) (P) for 24 hours. (Q and R) Tumor volume of LS513 xenografts (Q) and the body weights of the tumor-bearing nude mice (R) treated with vehicle, MS934 (50 mg/kg), lapatinib (100 mg/kg), or the combination. n = 5 mice per treatment group. In (A) to (R), blots and images are representative of three independent experiments, and quantified data are means ± SD [SEM in (Q) and (R)] of three independent experiments; ***P ≤ 0.001 by Student’s t test.

 

Fig. 7. Lapatinib treatment improves KRASG12C degrader therapies in MDR1-overexpressing CRC cell lines.
(A and B) Colony formation by SW1463 (A) or SW837 (B) cells treated with DMSO, LC-2 (1 μM), or MRTX849 (1 μM) for 14 days. Images representative of three independent assays. (C to E) Immunoblotting in SW1463 cells (C and D) and SW837 cells (E) treated with DMSO, LC-2 (1 μM), tariquidar (0.1 μM) (C), or lapatinib (5 μM) (D and E) alone or in combination for 48 hours. Blots are representative of three independent experiments. (F and G) Bliss synergy scores based on CellTiter-Glo assay for the cell viability of SW1463 (F) or SW837 (G) cells treated with increasing concentrations of LC-2, lapatinib, or the combination. Data are means of three experiments ± SD. (H and I) Colony formation of SW1463 (H) or SW837 (I) cells treated as indicated (−, DMSO; LC-2, 1 μM; lapatinib, 2 μM; tariquidar, 0.1 μM) for 14 days. Images representative of three independent assays. (J) Rationale for combining lapatinib with MEK1/2 or KRASG12C degraders in MDR1-overexpressing CRC cell lines. Simultaneous blockade of MDR1 and ErbB receptor signaling overcomes degrader resistance and ErbB receptor kinome reprogramming, resulting in sustained inhibition of KRAS effector signaling.

SOURCE

https://www.science.org/doi/10.1126/scisignal.abn2707

Other articles in this Open Access Scientific Journal on PROTAC therapy in cancer include

Accelerating PROTAC drug discovery: Establishing a relationship between ubiquitination and target protein degradation

The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery

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Accelerating PROTAC drug discovery: Establishing a relationship between ubiquitination and target protein degradation

Posted in Apoptosis, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Biomedical Measurement Science, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Childhood cancer, Enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP), KRAS Mutation, Li-fraumeni syndrome., Proteosome, TP53 - Germline mutations, Ubiquitin, tagged breast cancer, Cancer - General, E3 Ligase, high throughput, MDM2, PROTAC, TUBEs, Ubiquitin ligase, ubiquitin-proteosome, VHL on October 4, 2022| Leave a Comment »

Accelerating PROTAC drug discovery: Establishing a relationship between ubiquitination and target protein degradation

Curator: Stephen J. Williams, Ph.D.

PROTACs have been explored in multiple disease fields with focus on only few ligases like cereblon (CRBN), Von Hippel-Lindau (VHL), IAP and MDM2. Cancer targets like androgen receptor, estrogen receptor, BTK, BCL2, CDK8 and c-MET [[6], [7], [8], [9], [10], [11]] have been successfully targeted using PROTACs. A variety of BET family (BRD2, BRD3, and BRD4)- PROTACs were designed using multiple ligases; MDM2-based BRD4 PROTAC [12], CRBN based dBET1 [13] and BETd-24-6 [14] for triple-negative breast cancer, enhanced membrane permeable dBET6 [15], and dBET57 PROTAC [16]. PROTACs for Hepatitis c virus (HCV) protease, IRAK4 and Tau [[17], [18], [19]] have been explored for viral, immune and neurodegenerative diseases, respectively. Currently, the PROTAC field expansion to vast undruggable proteome is hindered due to narrow focus on select E3 ligases. Lack of reliable tools to rapidly evaluate PROTACs based on new ligases is hindering the progress. Screening platforms designed must be physiologically relevant and represent true PROTAC cellular function, i.e., PROTAC-mediated target ubiquitination and degradation.

In the current study, we employ TUBEs as affinity capture reagents to monitor PROTAC-induced poly-ubiquitination and degradation as a measure of potency. We established and validated proof-of-concept cell-based assays in a 96-well format using PROTACS for three therapeutic targets BET family proteins, kinases, and KRAS. To our knowledge, the proposed PROTAC assays are first of its kind that can simultaneously 1) detect ubiquitination of endogenous, native protein targets, 2) evaluate the potency of PROTACs, and 3) establish a link between the UPS and protein degradation. Using these TUBE assays, we established rank order potencies between four BET family PROTACs dBET1, dBET6, BETd246 and dBET57 based on peak ubiquitination signals (“Ub_Max”) of the target protein. TUBE assay was successful in demonstrating promiscuous kinase PROTACs efficiency to degrade Aurora Kinase A at sub-nanomolar concentrations within 1 h. A comparative study to identify changes in the ubiquitination and degradation profile of KRAS G12C PROTACs recruiting two E3 ligases (CRBN and VHL). All of the ubiquitination and degradation profiles obtained from TUBE based assays correlate well with traditional low throughput immunoblotting. Significant correlation between DC₅₀ obtained from protein degradation in western blotting and Ub_Max values demonstrates our proposed assays can aid in high-throughput screening and drastically eliminate artifacts to overcome bottlenecks in PROTAC drug discovery.

To successfully set up HTS screening with novel PROTACs without pre-existing knowledge, we recommend the following steps. 1. Identify a model PROTAC that can potentially demonstrate activity based on knowledge in PROTAC design or in vitro binding studies. 2. Perform a time course study with 2–3 doses of the model PROTAC based on affinities of the ligands selected. 3. Monitor ubiquitination and degradation profiles using plate-based assay and identify time point that demonstrates Ub_Max. 4. Perform a dose response at selected time point with a library of PROTACs to establish rank order potency.

INTRODUCTION

Ubiquitination is a major regulatory mechanism to maintain cellular protein homeostasis by marking proteins for proteasomal-mediated degradation [1]. Given ubiquitin’s role in a variety of pathologies, the idea of targeting the Ubiquitin Proteasome System (UPS) is at the forefront of drug discovery [2]. “Event-driven” protein degradation using the cell’s own UPS is a promising technology for addressing the “undruggable” proteome [3]. Targeted protein degradation (TPD) has emerged as a new paradigm and promising therapeutic option to selectively attack previously intractable drug targets using PROteolytic TArgeting Chimeras (PROTACs) [4]. PROTACs are heterobifunctional molecules with a distinct ligand that targets a specific E3 ligase which is tethered to another ligand specific for the target protein using an optimized chemical linker. A functional PROTAC induces a ternary E3-PROTAC-target complex, resulting in poly-ubiquitination and subsequent controlled protein degradation [5]. Ability to function at sub-stoichiometric levels for efficient degradation, a significant advantage over traditional small molecules.

PROTACs have been explored in multiple disease fields with focus on only few ligases like cereblon (CRBN), Von Hippel-Lindau (VHL), IAP and MDM2. Cancer targets like androgen receptor, estrogen receptor, BTK, BCL2, CDK8 and c-MET [[6], [7], [8], [9], [10], [11]] have been successfully targeted using PROTACs. A variety of BET family (BRD2, BRD3, and BRD4)- PROTACs were designed using multiple ligases; MDM2-based BRD4 PROTAC [12], CRBN based dBET1 [13] and BETd-24-6 [14] for triple-negative breast cancer, enhanced membrane permeable dBET6 [15], and dBET57 PROTAC [16]. PROTACs for Hepatitis c virus (HCV) protease, IRAK4 and Tau [[17], [18], [19]] have been explored for viral, immune and neurodegenerative diseases, respectively. Currently, the PROTAC field expansion to vast undruggable proteome is hindered due to narrow focus on select E3 ligases. Lack of reliable tools to rapidly evaluate PROTACs based on new ligases is hindering the progress. Screening platforms designed must be physiologically relevant and represent true PROTAC cellular function, i.e., PROTAC-mediated target ubiquitination and degradation.

Cellular PROTAC screening is traditionally performed using cell lines harboring reporter genes and/or Western blotting. While Western blotting is easy to perform, they are low throughput, semi-quantitative and lack sensitivity. While reporter gene assays address some of the issues, they are challenged by reporter tags having internal lysines leading to artifacts. Currently, no approaches are available that can identify true PROTAC effects such as target ubiquitination and proteasome-mediated degradation simultaneously. High affinity ubiquitin capture reagents like TUBEs [20] (tandem ubiquitin binding entities), are engineered ubiquitin binding domains (UBDs) that allow for detection of ultralow levels of polyubiquitinated proteins under native conditions with affinities as low as 1 nM. The versatility and selectivity of TUBEs makes them superior to antibodies, and they also offer chain-selectivity (-K48, -K63, or linear) [21]. High throughput assays that can report the efficacy of multiple PROTACs simultaneously by monitoring PROTAC mediated ubiquitination can help establish rank order potency and guide chemists in developing meaningful structure activity relationships (SAR) rapidly.

In the current study, we employ TUBEs as affinity capture reagents to monitor PROTAC-induced poly-ubiquitination and degradation as a measure of potency. We established and validated proof-of-concept cell-based assays in a 96-well format using PROTACS for three therapeutic targets BET family proteins, kinases, and KRAS. To our knowledge, the proposed PROTAC assays are first of its kind that can simultaneously 1) detect ubiquitination of endogenous, native protein targets, 2) evaluate the potency of PROTACs, and 3) establish a link between the UPS and protein degradation. Using these TUBE assays, we established rank order potencies between four BET family PROTACs dBET1, dBET6, BETd246 and dBET57 based on peak ubiquitination signals (“Ub_Max”) of the target protein. TUBE assay was successful in demonstrating promiscuous kinase PROTACs efficiency to degrade Aurora Kinase A at sub-nanomolar concentrations within 1 h. A comparative study to identify changes in the ubiquitination and degradation profile of KRAS G12C PROTACs recruiting two E3 ligases (CRBN and VHL). All of the ubiquitination and degradation profiles obtained from TUBE based assays correlate well with traditional low throughput immunoblotting. Significant correlation between DC₅₀ obtained from protein degradation in western blotting and Ub_Max values demonstrates our proposed assays can aid in high-throughput screening and drastically eliminate artifacts to overcome bottlenecks in PROTAC drug discovery.

 

 

 

 

 

 

 

 

 

SOURCE

https://www.sciencedirect.com/science/article/abs/pii/S0006291X22011792

Other articles of PROTACs in this Open Access Journal Include

The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery

Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

From High-Throughput Assay to Systems Biology: New Tools for Drug Discovery

 

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Global Alliance for Genomics and Health Issues Guidelines for Data Siloing and Sharing

Posted in Advanced Computing Platform, and Bioethics, Artificial Intelligence - Breakthroughs in Theories and Technologies, Artificial Intelligence Applications in Health Care, Big Data, Bio-Ethics, BioBanking, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biotechnology, Genome Biology, Health Economics and Outcomes Research, Health Law & Patient Safety, Health Law Policy, Intelligent Information Systems, Machine Learning, Personalized and Precision Medicine & Genomic Research, Personalized Medicine Coalition, tagged @science 2_0, Big data, biomedical, Cancer - General, curated database, data networks, data silos, European Union, GA4GH, Genomic data, genomics, NGS, Open data, scientific collaboration on December 14, 2021| Leave a Comment »

Reporter: Stephen J. Williams, Ph.D.

From: Heidi Rheim et al. GA4GH: International policies and standards for data sharing across genomic research and healthcare. (2021): Cell Genomics, Volume 1 Issue 2.

Source: DOI:https://doi.org/10.1016/j.xgen.2021.100029

Highlights

• Siloing genomic data in institutions/jurisdictions limits learning and knowledge
• GA4GH policy frameworks enable responsible genomic data sharing
• GA4GH technical standards ensure interoperability, broad access, and global benefits
• Data sharing across research and healthcare will extend the potential of genomics

Summary

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

The GA4GH organization and its strategies for addressing challenges of clinical and genomic #dataSharing https://t.co/a61HVLiKyD pic.twitter.com/ngdwecwEcd

— NCI Genomics (@NCIgenomics) November 17, 2021

In order for genomic and personalized medicine to come to fruition it is imperative that data siloes around the world are broken down, allowing the international collaboration for the collection, storage, transferring, accessing and analying of molecular and health-related data.

We had talked on this site in numerous articles about the problems data siloes produce. By data siloes we are meaning that collection and storage of not only DATA but intellectual thought are being held behind physical, electronic, and intellectual walls and inacessible to other scientisits not belonging either to a particular institituion or even a collaborative network.

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

Standardization and harmonization of data is key to this effort to sharing electronic records. The EU has taken bold action in this matter. The following section is about the General Data Protection Regulation of the EU and can be found at the following link:

https://ec.europa.eu/info/law/law-topic/data-protection/data-protection-eu_en

Fundamental rights

The EU Charter of Fundamental Rights stipulates that EU citizens have the right to protection of their personal data.

Protection of personal data

Legislation

The data protection package adopted in May 2016 aims at making Europe fit for the digital age. More than 90% of Europeans say they want the same data protection rights across the EU and regardless of where their data is processed.

The General Data Protection Regulation (GDPR)

Regulation (EU) 2016/679 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data. This text includes the corrigendum published in the OJEU of 23 May 2018.

The regulation is an essential step to strengthen individuals’ fundamental rights in the digital age and facilitate business by clarifying rules for companies and public bodies in the digital single market. A single law will also do away with the current fragmentation in different national systems and unnecessary administrative burdens.

The regulation entered into force on 24 May 2016 and applies since 25 May 2018. More information for companies and individuals.

Information about the incorporation of the General Data Protection Regulation (GDPR) into the EEA Agreement.

EU Member States notifications to the European Commission under the GDPR

The Data Protection Law Enforcement Directive

Directive (EU) 2016/680 on the protection of natural persons regarding processing of personal data connected with criminal offences or the execution of criminal penalties, and on the free movement of such data.

The directive protects citizens’ fundamental right to data protection whenever personal data is used by criminal law enforcement authorities for law enforcement purposes. It will in particular ensure that the personal data of victims, witnesses, and suspects of crime are duly protected and will facilitate cross-border cooperation in the fight against crime and terrorism.

The directive entered into force on 5 May 2016 and EU countries had to transpose it into their national law by 6 May 2018.

The following paper by the organiztion The Global Alliance for Genomics and Health discusses these types of collaborative efforts to break down data silos in personalized medicine. This organization has over 2000 subscribers in over 90 countries encompassing over 60 organizations.

Enabling responsible genomic data sharing for the benefit of human health

The Global Alliance for Genomics and Health (GA4GH) is a policy-framing and technical standards-setting organization, seeking to enable responsible genomic data sharing within a human rights framework.

he Global Alliance for Genomics and Health (GA4GH) is an international, nonprofit alliance formed in 2013 to accelerate the potential of research and medicine to advance human health. Bringing together 600+ leading organizations working in healthcare, research, patient advocacy, life science, and information technology, the GA4GH community is working together to create frameworks and standards to enable the responsible, voluntary, and secure sharing of genomic and health-related data. All of our work builds upon the Framework for Responsible Sharing of Genomic and Health-Related Data.

GA4GH Connect is a five-year strategic plan that aims to drive uptake of standards and frameworks for genomic data sharing within the research and healthcare communities in order to enable responsible sharing of clinical-grade genomic data by 2022. GA4GH Connect links our Work Streams with Driver Projects—real-world genomic data initiatives that help guide our development efforts and pilot our tools.

From the article on Cell Genomics GA4GH: International policies and standards for data sharing across genomic research and healthcare

Source: Open Access DOI:https://doi.org/10.1016/j.xgen.2021.100029PlumX Metrics

The Global Alliance for Genomics and Health (GA4GH) is a worldwide alliance of genomics researchers, data scientists, healthcare practitioners, and other stakeholders. We are collaborating to establish policy frameworks and technical standards for responsible, international sharing of genomic and other molecular data as well as related health data. Founded in 2013,³ the GA4GH community now consists of more than 1,000 individuals across more than 90 countries working together to enable broad sharing that transcends the boundaries of any single institution or country (see https://www.ga4gh.org).In this perspective, we present the strategic goals of GA4GH and detail current strategies and operational approaches to enable responsible sharing of clinical and genomic data, through both harmonized data aggregation and federated approaches, to advance genomic medicine and research. We describe technical and policy development activities of the eight GA4GH Work Streams and implementation activities across 24 real-world genomic data initiatives (“Driver Projects”). We review how GA4GH is addressing the major areas in which genomics is currently deployed including rare disease, common disease, cancer, and infectious disease. Finally, we describe differences between genomic sequence data that are generated for research versus healthcare purposes, and define strategies for meeting the unique challenges of responsibly enabling access to data acquired in the clinical setting.

GA4GH organization

GA4GH has partnered with 24 real-world genomic data initiatives (Driver Projects) to ensure its standards are fit for purpose and driven by real-world needs. Driver Projects make a commitment to help guide GA4GH development efforts and pilot GA4GH standards (see Table 2). Each Driver Project is expected to dedicate at least two full-time equivalents to GA4GH standards development, which takes place in the context of GA4GH Work Streams (see Figure 1). Work Streams are the key production teams of GA4GH, tackling challenges in eight distinct areas across the data life cycle (see Box 1). Work Streams consist of experts from their respective sub-disciplines and include membership from Driver Projects as well as hundreds of other organizations across the international genomics and health community.

Box 1GA4GH Work Stream focus areasThe GA4GH Work Streams are the key production teams of the organization. Each tackles a specific area in the data life cycle, as described below (URLs listed in the web resources).

• (1)Data use & researcher identities: Develops ontologies and data models to streamline global access to datasets generated in any country^9,10
• (2)Genomic knowledge standards: Develops specifications and data models for exchanging genomic variant observations and knowledge¹⁸
• (3)Cloud: Develops federated analysis approaches to support the statistical rigor needed to learn from large datasets
• (4)Data privacy & security: Develops guidelines and recommendations to ensure identifiable genomic and phenotypic data remain appropriately secure without sacrificing their analytic potential
• (5)Regulatory & ethics: Develops policies and recommendations for ensuring individual-level data are interoperable with existing norms and follow core ethical principles
• (6)Discovery: Develops data models and APIs to make data findable, accessible, interoperable, and reusable (FAIR)
• (7)Clinical & phenotypic data capture & exchange: Develops data models to ensure genomic data is most impactful through rich metadata collected in a standardized way
• (8)Large-scale genomics: Develops APIs and file formats to ensure harmonized technological platforms can support large-scale computing

For more articles on Open Access, Science 2.0, and Data Networks for Genomics on this Open Access Scientific Journal see:

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

eScientific Publishing a Case in Point: Evolution of Platform Architecture Methodologies and of Intellectual Property Development (Content Creation by Curation) Business Model 

UK Biobank Makes Available 200,000 whole genomes Open Access

Systems Biology Analysis of Transcription Networks, Artificial Intelligence, and High-End Computing Coming to Fruition in Personalized Oncology

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Researchers develop novel therapy that could be effective in many cancers

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Genomic Expression, Loss of function gene, therapeutics, tagged Akt, Cancer - General, Clinical trial, Drug discovery, health, medicine, Mount Sinai, MS21, novel therapeutic approach, Novella Clinical, research, therapeutics on July 29, 2021| Leave a Comment »

Reporter: Danielle Smolyar, Research Assistant 3 – Text Analysis for 2.0 LPBI Group’s TNS #1 – 2020/2021 Academic Internship in Medical Text Analysis (MTA)

Recently, researchers at Mount Sinai were able to develop a therapeutic agent that shows high levels of effectiveness in Vitro disrupting a biological pathway that allow cancer to survive. This finding is according to a paper which was published in Cancer Discovery, which is a Journal of the American Association of cancer research in July 2021.

The therapy in which they focus on is a molecule named MS21, which causes the degradation of AKT which is an enzyme that is very active and present in cancers. In this study there was much evidence that pharmacological degradation of AKT is a feasible treatment for cancer’s which have a mutation in certain genes. 

AKT is a cancer gene that encodes an enzyme that is abnormally activated in cancer cells to stimulate tumor growth. The degradation of AKT reverses all these processes which ultimately inhibits further tumor growth.

“Our study lays a solid foundation for the clinical development of an AKT degrader for the treatment of human cancers with certain gene mutations,” said Ramon Parsons, MD, Ph.D., Director of The Tisch Cancer Institute and Ward-Coleman Chair in Cancer Research and Chair of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. “Examination of 44,000 human cancers identified that 19 percent of tumors have at least one of these mutations, suggesting that a large population of cancer patients could benefit from therapy with an AKT degrader such as MS21.”

https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html.

MS21 was tested and human cancer derived cell lines, is used in Laboratories as a model to study the efficacy of different cancer therapies.

At Mount Sinai they were looking to develop MS21 with an industry partner in order to open clinical trials for patients. 

“Translating these findings into effective cancer therapies for patients is a high priority because the mutations and the resulting cancer-driving pathways that we lay out in this study are arguably the most commonly activated pathways in human cancer, but this effort has proven to be particularly challenging,” said Jian Jin, Ph.D., Mount Sinai Professor in Therapeutics Discovery and Director of the Mount Sinai Center for Therapeutics Discovery at Icahn Mount Sinai. “We look forward to an opportunity to develop this molecule into a therapy that is ready to be studied in clinical trials.”

https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html.

Image credit: National Cancer Institute

Original article: 

https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html

Researchers develop novel therapy that could be effective in many cancers

staff, S. X. (2021, July 23). R. Medical Xpress – by The Mount Sinai Hospital

https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html. 

https://www.eurekalert.org/news-releases/779594

UPDATE 12/12/2022

From Mt. Sinai

Advancing cancer precision medicine by creating a better toolbox for cancer therapy

Jian Jin1,2,3,4,5*, Arvin C. Dar1,2,3,4, Deborah Doroshow¹

A

mong approximately 20,000 proteins in the human proteome, 627 have been identified by cancer-dependency studies as priority can­cer targets, which are functionally important for various cancers. Of these 600-plus priority targets, 232 are enzymes and 395 are nonenzyme proteins (1). Tremendous progress has been made over the past several decades in targeting enzymes, in particular kinas-es, which have suitable binding pockets that can be occupied by small-molecule inhibitors, leading to U.S. Food and Drug Administration (FDA) approvals of many small-molecule drugs as targeted anticancer thera-

¹Tisch Cancer Institute; ²Department of Oncological Sciences; ³Department of Pharmacological Sciences; ⁴Mount Sinai Center for Therapeutics Discovery; ⁵Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY

*Corresponding author: jian.jin@mssm.edu

10

pies. However, most of the 395 nonenzyme protein targets, including tran­scription factors (TFs), do not have suitable binding pockets that can be effectively targeted by small molecules. These targets have consequently been considered undruggable; however, new cutting-edge approaches and technologies have recently been developed to target some of these “un-druggable” proteins in order to advance precision oncology.

TPD, a promising approach to precision cancer therapeutics

Targeted protein degradation (TPD) refers to the process of chemical­ly eliminating proteins of interest (POIs) by utilizing small molecules, which are broadly divided into two types of modalities: PROteolysis Tar­geting Chimeras (PROTACs) and molecular glues (2). PROTACs are het-erobifunctional small molecules that contain two moieties: one binding the POI, linked to another binding an ubiquitin E3 ligase. The induced proximity between the POI and ubiquitination machinery leads to selec­tive polyubiquitylation of the POI and its subsequent degradation by the ubiquitin–proteasome system (UPS). Molecular glues are monovalent small molecules, which, when built for TPD, directly induce interactions between the POI and an E3 ligase, also resulting in polyubiquitylation and subsequent degradation of the POI by the UPS. One of the biggest poten­tial advantages of these therapeutic modalities over traditional inhibitors is that PROTACs and molecular glues can target undruggable proteins. Explosive growth has been seen in the TPD field over recent years (2, 3). Here, we highlight several recent advancements.

TF-PROTAC, a novel platform for targeting undruggable

tumorigenic TFs

Many undruggable TFs are tumorigenic. To target them, TF-PROTAC was developed (4), which exploits the fact that TFs bind DNA in a sequence-specific manner. TF-PROTAC was created to selectively bind a TF and E3 ligase simultaneously, by conjugating a DNA oligonucleotide specific for the TF of interest to a selective E3 ligase ligand. As stated ear­lier, this simultaneous binding and induced proximity leads to selective polyubiquitination of the TF and its subsequent degradation by the UPS. TF-PROTAC is a cutting-edge technology that could potentially provide a universal strategy for targeting most undruggable tumorigenic TFs.

Development of novel PROTAC degraders

WDR5, an important scaffolding protein, not an enzyme, is essential for sustaining tumorigenesis in multiple cancers, including MLL-rearranged (MLL-r) leukemia. However, small-molecule inhibitors that block the pro-tein–protein interaction (PPI) between WDR5 and its binding partners ex­hibit very modest cancer cell–killing effects, likely due to the confounding fact that these PPI inhibitors target only some—but not all—of WDR5’s on-cogenic functions. To address this shortcoming, a novel WDR5 PROTAC, MS67, was recently created using a powerful approach that effectively eliminates the protein and thereby all WDR5 functions via ternary com­plex structure-based design (Figure 1) (5). MS67 is a highly effective WDR5 degrader that potently and selectively degrades WDR5 and effec­tively suppresses the proliferation of tumor cells both in vitro and in vivo. This study provides strong evidence that pharmacological degradation of WDR5 as a novel therapeutic strategy is superior to WDR5 PPI inhibition for treating WDR5-dependent cancers.

EZH2 is an oncogenic methyltransferase that catalyzes histone H3 ly­sine 27 trimethylation, mediating gene repression. In addition to this ca­nonical function, EZH2 has numerous noncanonical tumorigenic func­tions. EZH2 enzymatic inhibitors, however, are generally ineffective in

suppressing tumor growth in triple-negative breast cancer (TNBC) and MLL-r leukemia models and fail to phenocopy antitumor effects induced by EZH2 knockdown strategies. To target both canonical and noncanon-ical oncogenic functions of EZH2, several novel EZH2 degraders were recently developed, including MS1943, a hydrophobic tag–based EZH2 degrader (6), and MS177, an EZH2 PROTAC (7). MS1943 and MS177 effectively degrade EZH2 and suppress in vitro and in vivo growth in TNBC and MLL-r leukemia, respectively, suggesting that EZH2 degrad­ers could provide a novel and effective therapeutic strategy for EZH2-dependent tumors.

MS21, a novel AKT PROTAC degrader, was developed to target acti­vated AKT, the central node of the PI3K–AKT–mTOR signaling pathway (8). MS21 effectively suppresses the proliferation of PI3K–PTEN pathway-mutant cancers with wild-type KRAS and BRAF, which represent a large percentage of all human cancers. Another recent technology that expands the bifunctional toolbox for TPD is the demonstration that the E3 ligase KEAP1 can be leveraged for PROTAC development using a selective KEAP1 ligand (9). Overall, tremendous progress has been made in discov­ering novel degraders, some of which have advanced to clinical develop­ment as targeted therapies (2, 3).

Novel approaches to selective TPD in cancer cells

To minimize uncontrolled protein degradation in normal tissues, which may cause potential toxicity, a new technology was developed that incor­porates a light-inducible switch, termed “opto-PROTAC” (10). This switch serves as a caging group that renders opto-PROTAC inactive in all cells in the absence of ultraviolet (UV) light. Upon UV irradiation, however, the caging group is removed, resulting in the release of the active degrader and spatiotemporal control of TPD in cancer cells. Another strategy to achieve selective TPD in cancer over normal cells is to cage degraders with a folate group (11, 12). Folate-caged degraders are inert and selectively concen­trated within cancer cells, which overexpress folate receptors compared to normal cells. The caging group is subsequently removed inside tumor cells, releasing active degraders and achieving selective TPD in these cells. These novel approaches potentially enable degraders to be precision can­cer medicines.

11

Frontiers of Medical Research: Cancer

Trametiglue, a novel and atypical molecular glue

The RAS–RAF–MEK–ERK signaling pathway, one of the most frequent­ly mutated pathways in cancer, has been intensively targeted. Several drugs, such as the KRAS G12C inhibitor sotorasib and the MEK inhib­itor trametinib, have been approved by the FDA. A significant advance­ment in this area is the discovery that trametinib unexpectedly binds a pseudokinase scaffold termed “KSR” in addition to MEK through inter­facial contacts (13). Based on this structural and mechanistic insight, tra-metiglue, an analog of trametinib, was created as a novel molecular glue to limit adaptive resistance to MEK inhibition by enhancing interfacial binding between MEK, KSR, and the related homolog RAF. This study provides a strong foundation for developing next-generation drugs that target the RAS pathway.

TF-DUBTAC, a novel technology to stabilize undruggable tumor-suppressive TFs

Complementary to degrading tumorigenic TFs, stabilizing tumor-suppressive TFs could provide another effective approach for treating can­cer. While most tumor-suppressive TFs are undruggable, TF-DUBTAC was recently developed as a generalizable platform to stabilize tumor-sup­pressive TFs (14). Deubiquitinase-targeting chimeras (DUBTACs) are heterobifunctional small molecules with a deubiquitinase (DUB) ligand linked to a POI ligand, which stabilize POIs by harnessing the deubiq-uitination machinery (15). Similar to TF-PROTAC, TF-DUBTAC exploits the fact that most TFs bind specific DNA sequences. TF-DUBTAC links a DNA oligonucleotide specific to a tumor-suppressive TF with a selective DUB ligand, resulting in simultaneous binding of the TF and DUB. The induced proximity between the TF and DUB leads to selective deubiquiti-

Putting a bull’s-eye on cancer’s back

Scientists are aiming the immune systems’ “troops” directly at tumors to better treat cancer

Joshua D. Brody, Brian D. Brown

I

mmunotherapy has transformed the treatment of several types of can­cers. In particular, immune checkpoint blockade (ICB), which reinvig­orates killer T cells, has helped extend the lives of many patients with advanced-stage lung, bladder, kidney, or skin cancers. Unfortunately, ~80% of patients do not respond to current immunotherapies or even-tually relapse. Emerging data indicate that one of the most profound ways cancers resist immunotherapy is by keeping killer T cells out of the tumor and putting other immune cells in a suppressed state (1). This un­derstanding is giving rise to a new frontier in immunotherapy that is using synthetic biology and other approaches to reprogram the tumor from im­mune “cold” to immune “hot,” so T cells can be recruited to the tumor, and enter, target, and destroy the cancer cells (2) (Figure 1).

Cancers protect themselves by keeping out immune cells

Cancers grow in tissues like foreign invaders. Though they start from healthy cells, mutations turn cells malignant and allow them to grow un­checked. T cells can kill malignant cells that express mutated proteins, but cancers employ strategies to fend off the T cells. One way they do this is

12

nation of the TF and its stabilization. As an exciting new technology, TF-DUBTAC provides a potential general strategy to stabilize most undrugga-ble tumor-suppressive TFs for treating cancer.

Future outlook

The breathtaking pace we are seeing in the development of innovative approaches and technologies for advancing cancer therapies is only ex­pected to accelerate. The promising clinical results achieved by PROTACs with established targets are particularly encouraging and pave the way for development of PROTACs for newer and more innovative targets. These groundbreaking discoveries have now put opportunities to fully realize cancer precision medicine within our reach.

References

1. F. M. Behan et al., Nature 568, 511–516 (2019).
2. B. Dale et al., Nat. Rev. Cancer 21, 638–654 (2021).
3. A. Mullard, Nat. Rev. Drug Discov. 20, 247–250 (2021).
4. J. Liu et al., J. Am. Chem. Soc. 143, 8902–8910 (2021).
5. X. Yu et al., Sci. Transl. Med. 13, eabj1578 (2021).
6. A. Ma et al., Nat. Chem. Biol. 16, 214–222 (2020).
7. J. Wang et al., Nat. Cell Biol. 24, 384–399 (2022).
8. J. Xu et al., Cancer Discov. 11, 3064–3089 (2021).
9. J. Wei et al., J. Am. Chem. Soc. 143, 15073–15083 (2021).
10. J. Liu et al., Sci. Adv. 6, eaay5154 (2020).
11. J. Liu et al., J. Am. Chem. Soc. 143, 7380–7387 (2021).
12. H. Chen et al., J. Med. Chem. 64, 12273–12285 (2021).
13. Z. M. Khan et al., Nature 588, 509–514 (2020).
14. J. Liu et al., J. Am. Chem. Soc. 144, 12934–12941 (2022).

N. J. Henning et al., Nat. Chem. Biol. 18, 412–421 (2022

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Machine Learning (ML) in cancer prognosis prediction helps the researcher to identify multiple known as well as candidate cancer diver genes

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#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

Posted in BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Cancer - General, Cancer and Current Therapeutics, Cancer Genomics, Cancer Informatics, Cancer Prevention: Research & Programs, Molecular Genetics & Pharmaceutical, Uncategorized, tagged Cancer - General, Cancer research, science, Technology, Translational Research on January 8, 2019| Leave a Comment »

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

Reporter: Gail S. Thornton

 

News announced during the 37th J.P. Morgan Healthcare Conference (#JPM19): Drugmaker Eli Lilly and Company announced its plans to acquire Loxo for $8 billion, as part of its oncology strategy, which focuses  “opportunities for first-in-class and best-in-class therapies.”   

 

Please read their press release below.

---

INDIANAPOLIS and STAMFORD, Conn., Jan. 7, 2019 /PRNewswire/ —

• Acquisition will broaden the scope of Lilly’s oncology portfolio into precision medicines through the addition of a marketed therapy and a pipeline of highly selective potential medicines for patients with genomically defined cancers.
• Loxo Oncology’s pipeline includes LOXO-292, an oral RET inhibitor being studied across multiple tumor types, which recently was granted Breakthrough Therapy designation by the FDA and could launch in 2020.
• Loxo Oncology’s Vitrakvi® (larotrectinib) is an oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the FDA.
• Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of$235.00 per share in cash, or approximately $8.0 billion.
• Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST.

Eli Lilly and Company (NYSE: LLY) and Loxo Oncology, Inc. (NASDAQ: LOXO) today announced a definitive agreement for Lilly to acquire Loxo Oncology for $235.00 per share in cash, or approximately $8.0 billion. Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers.

The acquisition would be the largest and latest in a series of transactions Lilly has conducted to broaden its cancer treatment efforts with externally sourced opportunities for first-in-class and best-in-class therapies. Loxo Oncology is developing a pipeline of targeted medicines focused on cancers that are uniquely dependent on single gene abnormalities that can be detected by genomic testing.  For patients with cancers that harbor these genomic alterations, a targeted medicine could have the potential to treat the cancer with dramatic effect.

Loxo Oncology has a promising portfolio of approved and investigational medicines, including:

• LOXO-292, a first-in-class oral RET inhibitor that has been granted Breakthrough Therapy designation by the FDA for three indications, with an initial potential launch in 2020.  LOXO-292 targets cancers with alterations to the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types, including certain lung and thyroid cancers as well as a subset of other cancers.
• LOXO-305, an oral BTK inhibitor currently in Phase 1/2. LOXO-305 targets cancers with alterations to the Bruton’s tyrosine kinase (BTK), and is designed to address acquired resistance to currently available BTK inhibitors. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas.
• Vitrakvi, a first-in-class oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the U.S. Food and Drug Administration (FDA). Vitrakvi is the first treatment that targets a specific genetic abnormality to receive a tumor-agnostic indication at the time of initial FDA approval.
• LOXO-195, a follow-on TRK inhibitor also being studied by Loxo Oncology and Bayer for acquired resistance to TRK inhibition, with a potential launch in 2022.

“Using tailored medicines to target key tumor dependencies offers an increasingly robust approach to cancer treatment,” said Daniel Skovronsky, M.D., Ph.D., Lilly’s chief scientific officer and president of Lilly Research Laboratories. “Loxo Oncology’s portfolio of RET, BTK and TRK inhibitors targeted specifically to patients with mutations or fusions in these genes, in combination with advanced diagnostics that allow us to know exactly which patients may benefit, creates new opportunities to improve the lives of people with advanced cancer.”

“We are gratified that Lilly has recognized our contributions to the field of precision medicine and are excited to see our pipeline benefit from the resources and global reach of the Lilly organization,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “Tumor genomic profiling is becoming standard-of-care, and it will be critical to continue innovating against new targets, while anticipating mechanisms of resistance to available therapies, so that patients with advanced cancer have the chance to live longer and better lives.”

“Lilly Oncology is committed to developing innovative, breakthrough medicines that will make a meaningful difference for people with cancer and help them live longer, healthier lives,” said Anne White, president of Lilly Oncology. “The acquisition of Loxo Oncology represents an exciting and immediate opportunity to expand the breadth of our portfolio into precision medicines and target cancers that are caused by specific gene abnormalities. The ability to target tumor dependencies in these populations is a key part of our Lilly Oncology strategy. We look forward to continuing to advance the pioneering scientific innovation begun by Loxo Oncology.”

“We are excited to have reached this agreement with a team that shares our commitment to ensuring that emerging translational science reaches patients in need,” said Jacob Van Naarden, chief operating officer of Loxo Oncology. “We are confident that the work we have started, which includes an FDA approved drug, and a pipeline spanning from Phase 2 to discovery, will continue to thrive in Lilly’s hands.”

Under the terms of the agreement, Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of $235.00 per share in cash, or approximately $8.0 billion. The transaction is not subject to any financing condition and is expected to close by the end of the first quarter of 2019, subject to customary closing conditions, including receipt of required regulatory approvals and the tender of a majority of the outstanding shares of Loxo Oncology’s common stock. Following the successful closing of the tender offer, Lilly will acquire any shares of Loxo Oncology that are not tendered into the tender offer through a second-step merger at the tender offer price.

The tender offer represents a premium of approximately 68 percent to Loxo Oncology’s closing stock price on January 4, 2019, the last trading day before the announcement of the transaction. Loxo Oncology’s board recommends that Loxo Oncology’s shareholders tender their shares in the tender offer.  Additionally, a Loxo Oncology shareholder, beneficially owning approximately 6.6 percent of Loxo Oncology’s outstanding common stock, has agreed to tender its shares in the tender offer.

This transaction will be reflected in Lilly’s financial results and financial guidance according to Generally Accepted Accounting Principles (GAAP). Lilly will provide an update to its 2019 financial guidance, including the expected impact from the acquisition of Loxo Oncology, as part of its fourth-quarter and full-year 2018 financial results announcement on February 13, 2019.

For Lilly, Deutsche Bank is acting as the exclusive financial advisor and Weil, Gotshal & Manges LLP is acting as legal advisor in this transaction. For Loxo Oncology, Goldman Sachs & Co. LLC is acting as exclusive financial advisor and Fenwick & West LLP is acting as legal advisor.

Conference Call and Webcast
Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST to discuss the acquisition of Loxo Oncology.  Investors, media and the general public can access a live webcast of the conference call through the Webcasts & Presentations link that will be posted on Lilly’s website at www.lilly.com.  The webcast of the conference call will be available for replay through February 7, 2019.

About LOXO-292
LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. LOXO-292 has been granted Breakthrough Therapy Designation by the U.S. FDA for three indications, and could launch as early as 2020.

About LOXO-305
LOXO-305 is an investigational, highly selective non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma.

About Vitrakvi^® (larotrectinib)
Vitrakvi is an oral TRK inhibitor for the treatment of adult and pediatric patients with solid tumors with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

About LOXO-195
LOXO-195 is a selective TRK inhibitor that is being investigated to address potential mechanisms of acquired resistance that may emerge in patients receiving Vitrakvi^® (larotrectinib) or other multikinase inhibitors with anti-TRK activity.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and www.lilly.com/newsroom/social-channels. C-LLY

About Loxo Oncology
Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers. Our pipeline focuses on cancers that are uniquely dependent on single gene abnormalities, such that a single drug has the potential to treat the cancer with dramatic effect. We believe that the most selective, purpose-built medicines have the highest probability of maximally inhibiting the intended target, with the intention of delivering best-in-class disease control and safety. Our management team seeks out experienced industry partners, world-class scientific advisors and innovative clinical-regulatory approaches to deliver new cancer therapies to patients as quickly and efficiently as possible. For more information, please visit the company’s website at http://www.loxooncology.com.

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements about the benefits of Lilly’s acquisition of Loxo Oncology, Inc. (“Loxo Oncology”). It reflects Lilly‘s current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in implementing the transaction and in drug development. Among other things, there can be no guarantee that the transaction will be completed in the anticipated timeframe, or at all, or that the conditions required to complete the transaction will be met, that Lilly will realize the expected benefits of the transaction, that the molecules will be approved on the anticipated timeline or at all, or that the potential products will be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly‘s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission (“the SEC”). Lilly will provide an update to certain elements of its 2019 financial guidance as part of its fourth quarter and full-year 2018 financial results announcement. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

Loxo Oncology Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” relating to the acquisition of Loxo Oncology by Lilly. Such forward-looking statements include the ability of Loxo Oncology and Lilly to complete the transactions contemplated by the merger agreement, including the parties’ ability to satisfy the conditions to the consummation of the offer and the other conditions set forth in the merger agreement and the possibility of any termination of the merger agreement, as well as the role of targeted genomics and diagnostics in oncology treatment and acceleration of our work in developing medicines. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. Actual results may differ materially from current expectations because of risks associated with uncertainties as to the timing of the offer and the subsequent merger; uncertainties as to how many of Loxo Oncology’s stockholders will tender their shares in the offer; the risk that competing offers or acquisition proposals will be made; the possibility that various conditions to the consummation of the offer or the merger may not be satisfied or waived; the effects of disruption from the transactions contemplated by the merger agreement on Loxo Oncology’s business and the fact that the announcement and pendency of the transactions may make it more difficult to establish or maintain relationships with employees, suppliers and other business partners; the risk that stockholder litigation in connection with the offer or the merger may result in significant costs of defense, indemnification and liability; other uncertainties pertaining to the business of Loxo Oncology, including those set forth in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of Loxo Oncology’s Annual Report on Form 10-K for the year ended December 31, 2017, which is on file with the SEC and available on the SEC’s website at www.sec.gov. Additional factors may be set forth in those sections of Loxo Oncology’s Quarterly Report on Form 10-Q for the quarter endedSeptember 30, 2018, filed with the SEC in the fourth quarter of 2018.  In addition to the risks described above and in Loxo Oncology’s other filings with the SEC, other unknown or unpredictable factors could also affect Loxo Oncology’s results. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. The information contained in this press release is provided only as of the date of this report, and Loxo Oncology undertakes no obligation to update any forward-looking statements either contained in or incorporated by reference into this report on account of new information, future events, or otherwise, except as required by law.

Additional Information about the Acquisition and Where to Find It

The tender offer for the outstanding shares of Loxo Oncology referenced in this communication has not yet commenced. This announcement is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell shares of Loxo Oncology, nor is it a substitute for the tender offer materials that Lilly and its acquisition subsidiary will file with the SEC upon commencement of the tender offer. At the time the tender offer is commenced, Lilly and its acquisition subsidiary will file tender offer materials on Schedule TO, and Loxo Oncology will file a Solicitation/Recommendation Statement on Schedule 14D-9 with the SEC with respect to the tender offer. THE TENDER OFFER MATERIALS (INCLUDING AN OFFER TO PURCHASE, A RELATED LETTER OF TRANSMITTAL AND CERTAIN OTHER TENDER OFFER DOCUMENTS) AND THE SOLICITATION/RECOMMENDATION STATEMENT WILL CONTAIN IMPORTANT INFORMATION. HOLDERS OF SHARES OF LOXO ONCOLOGY ARE URGED TO READ THESE DOCUMENTS CAREFULLY WHEN THEY BECOME AVAILABLE (AS EACH MAY BE AMENDED OR SUPPLEMENTED FROM TIME TO TIME) BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION THAT HOLDERS OF LOXO ONCOLOGY SECURITIES SHOULD CONSIDER BEFORE MAKING ANY DECISION REGARDING TENDERING THEIR SECURITIES. The Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, will be made available to all holders of shares of Loxo Oncology at no expense to them. The tender offer materials and the Solicitation/Recommendation Statement will be made available for free at the SEC’s web site at www.sec.gov. 

In addition to the Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, Lilly and Loxo Oncology file annual, quarterly and special reports and other information with the SEC.  You may read and copy any reports or other information filed by Lilly or Loxo Oncology at the SEC public reference room at 100 F Street, N.E., Washington, D.C. 20549. Please call the Commission at 1-800-SEC-0330 for further information on the public reference room.  Lilly’s and Loxo Oncology’s filings with the SEC are also available to the public from commercial document-retrieval services and at the website maintained by the SEC at www.sec.gov.

SOURCE

Eli Lilly and Company – https://www.lilly.com

Other related articles published in this Open Access Online Scientific Journal include the following:

2017

FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)

https://pharmaceuticalintelligence.com/2017/08/30/fda-has-approved-the-worlds-first-car-t-therapy-novartis-for-kymriah-tisagenlecleucel-and-gileads-12-billion-buy-of-kite-pharma-no-approved-drug-and-canakinumab-for-lung-cancer-may-be/

2016

Pioneers of Cancer Cell Therapy:  Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

https://pharmaceuticalintelligence.com/2016/08/19/pioneers-of-cancer-cell-therapy-turbocharging-the-immune-system-to-battle-cancer-cells-success-in-hematological-cancers-vs-solid-tumors/

2015

Personalized Medicine – The California Initiative

https://pharmaceuticalintelligence.com/2015/10/12/personalized-medicine/

2013

Volume One: Genomics Orientations for Personalized Medicine

https://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-one-genomics-orientations-for-personalized-medicine/

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Nathalie’s Story: A Health Journey With A Happy Ending

Posted in Cancer - General, Cancer and Current Therapeutics, Cancer Prevention: Research & Programs, Patient Experience: Personal Memories of Invasive Medical Intervantion, Patient’s Voice: Personal Experience with Invasive Medical Procedures, Uncategorized, tagged Cancer - General, Patient, physician-patient relationship on July 30, 2016| Leave a Comment »

Nathalie’s Story: A Health Journey With A Happy Ending

Patient was diagnosed with adenocarcinoma of the duodenum over two years ago and had tumor removed at age 35. Interview was conducted 2+ years post-surgery.

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

 

Nathalie Monette of Laval, the third largest city in Quebec, Canada, counts her blessings each and every day. The 35-year-old is looking forward to making her mark on a bright and promising future as a newly married woman with a supportive family, new job as head of internal communications for a public service organization, and a new lease on life. Diagnosed a little over two years ago with a rare cancer called adenocarcinoma of the duodenum, Nathalie never envisioned that her life would take many twists and turns before she and her doctors arrived at an optimal treatment regimen.

Nathalie describes some of the classic warning signs she had for about six months before her actual medical diagnosis: abdominal cramping, nausea, vomiting, acid reflux and loss of weight.

“I felt sick all the time. I was losing weight and had pain in my upper abdomen after eating. My condition was getting worse with each week. My boyfriend, Jeff, at the time, who is now my husband, took me to several doctors who initially listened to my list of symptoms, examined me and told me to take antacids and avoid stress – and sent me home. It was increasingly becoming more difficult to manage my life, my relationships, and my job.”

The doctors in one hospital that she visited even considered she might be having a cardiovascular incident, since she was vomiting, was nauseous and had a stomach ache. Her blood levels were normal, which didn’t help the doctors, who, again, could find no serious health issue and sent her home.

Image SOURCE: Photographs courtesy of Nathalie Monette on the day of her wedding to Jeff. Top Left: Nathalie with her parents, Céline and Jean-Claude. Top Right: Nathalie with Jeff, and her two sisters, Julie and Marie-Claude. Below Right: Nathalie and Jeff.

For the next few weeks, Nathalie visited hospital after hospital in search of finding a more steadfast diagnosis of her condition – and a doctor who would listen to her and treat her symptoms.

“I was weak and vomiting. At this point, I kept losing weight — about 40 pounds in a total of six months.”

She decided to take the situation in her own hands and changed her diet, eliminating gluten, spices, and other major food groups. Nothing seemed to relieve her symptoms. She knew reading about possible medical conditions on the internet could cause additional stress. Having worked in the pharmaceutical industry, she was glad she knew where to look and what sources of information could be trusted.

Continued Search For Answers

“The medical system in Quebec is complicated,” she said. “In this public system, there is no family doctor assigned to you who follows your care year after year. And since I was perceived by the system as a young, relatively healthy woman, I was put on a waiting list for 3 to 4 years to be assigned to a general practitioner.”

Frustrated, hopeless and fearful for her health, Jeff got more involved in her diagnosis and took her to yet another hospital. Nathalie’s search took her from hospital to hospital and doctor to doctor with no known diagnosis.

“I was very angry, disappointed and at the end my rope. I just wanted to feel better and live my life.”

Then, one day, there was a ray of hope – and it took six months to find it. At a nearby hospital called Hôpital de St-Eustache where Jeff decided to take her, she came across two young physicians, Dr. Annie-Claude Bergeron, an emergency room doctor, and Dr. Marie-Hélène Gingras, a gastroenterologist, who happened to be Nathalie’s same age. Dr. Bergeron listened to her symptoms, examined her, and was determined to help her. A day later, Dr. Gingras ran several diagnostic tests, including an endoscopy and ultrasound, and more specialized blood tests.

“While undergoing the endoscopy, the doctor couldn’t find anything remarkable and was about to remove it. She decided to push the camera 5cm farther into my duodenum – and found the cause of my illness.”

Finally, Nathalie had definitive results. She had a 3½ cm (1.4 inches) tumor in her duodenum.

Dr. Gingras was devastated by the news she had to share. She called specialists in Montreal who would operate on Nathalie. Dr. Simon Turcotte, physician, hepatopancreatobiliary and liver transplantation expert who specializes in gastrointestinal cancer immunobiology and solid tumor immunotherapy, took her case.

“When Dr. Gingras told me about my condition, I was relieved and afraid at the same time. My heart sank when I got the news.”

Nathalie had a rare cancerous condition that only shows up in a handful of older people. It also was unusual that the tumor was situated in the duodenum rather than the colon, where most tumors of this variety normally occur. She also didn’t have history of that type of cancer in her family. She couldn’t even be tested for any genetic markers, since no genes have been identified as markers for this rare condition.

So, three weeks later, Nathalie was transferred to Hôpital Saint-Luc in Montreal, for a, hopefully, life-saving surgery. She had to trust her new expert, Dr. Turcotte, with her life.

“There was no room for error in removing the tumor. It was situated 1mm from my pancreas and every other vital organ I needed to survive.”

By nature, Nathalie is a strong, fiercely independent woman and there was no doubt she would come through the operation with flying colors.

About one month after surgery, she was scheduled for six months of chemotherapy to ensure that the cancer was eradicated. One day every two weeks, she received a powerful cocktail of Folfox (Leucovorin®, 5-FU, Adrucil® and Eloxatin®).

“Because of the chemotherapy, I had a minimal appetite, could not taste any food, could not drink or touch anything cold and needed to keep my weight at the same level.”

Her parents, Céline and Jean-Claude, two sisters, Julie and Marie-Claude, and Jeff, of course — were of great support and encouragement for her. Jeff insisted to meet with her nutritionist to determine a health plan so that she received the necessary nutrients in her food. Because Nathalie could not taste any food because of the chemotherapy, she tricked her mind by eating meals that she remembered from her childhood days. In that way, she was transported back in time mentally and she thought about the great food she had when she was growing up. Her parents were always on hand to cook these traditional meals that were filled with protein, spices, salt and fat to give her the added boost (and some taste) to help her system recover.

Duodenum, A Complex, Powerful Organ

Nathalie describes the duodenum as a complex organ – a C-shaped, hollow tube about 25-38 cm (10-15 inches) long, largely responsible for the enzymatic breakdown of food in the small intestine.

“This small but powerful organ is the shortest part of the small intestine which regulates the rate of how the stomach empties.”

According to the Inner Body web site, the duodenum receives partially digested food, called chyme, from the stomach and plays a vital role in the chemical digestion of chyme in preparation for absorption in the small intestine. Many chemical secretions from the pancreas, liver and gallbladder mix with the chyme in the duodenum to help chemical digestion. http://www.innerbody.com/image_dige02/dige21.html

Back to Normal

Nathalie’s life is back to normal, as much as it can be after such a medical ordeal.

“The past is just the past. I try not to think about the trauma that I’ve been through. I look forward as that is what is important.”

She got married last August (2015) to Jeff, who demonstrated his love to her the best way possible in caring for her throughout this ordeal. They met on the internet in 2010, at a moment when Nathalie wanted to leave the dating scene to focus on personal projects. They talked, met shortly after, and became great friends. Only a year later did Nathalie accept to be in a relationship with Jeff.

“About one week after my surgery when I was home, Jeff proposed marriage to me. I was visiting my family for Easter and Jeff had prepared everything. He had first asked my parents for my hand in marriage in the hospital a few weeks prior to my surgery. Then he prepared a charade with answers that related to the strength of his feelings for me. Funny enough, I did not understand what was going on at that point. Little did I know, he was declaring his love and it’s when he showed me a ring that I understood. Of course, I was overwhelmed with emotion and very touched that he got my family involved in the event.

“I am under regular care of my medical team of seven doctors – a gastroenterologist, oncologist surgeon, family general practitioner and many other specialists. I’ve had follow-up appointments at three months, six months, and one year. Those appointments include a gastroscopy, colonoscopy, scan, and blood tests, and so far, my health is the best ever. I like to tease the doctors when I see my charts – I look like an athlete on paper! In our Canadian medical system, each specialist treats only that part of the body. I make sure that all my test results are xeroxed and sent in advance of my appointment to each doctor. That takes time, but I am assured that everyone sees the same test results and can make educated decisions. That also makes for a more holistic view of my life.”

Advocate for Patient’ Rights

“Knowledge, access to information and caregiver support are probably the three most important factors in patient care. Medicine on its own is just not enough. Patients need a support system to balance out the highs and lows of searching through a medical condition, diagnosis and treatment plan. I hope one day to advocate for patient voices as it is a much needed part of our medical system.

“In hindsight, I realize all the doctors who saw me during the six months that I suffered prior to my diagnosis could not have known about my condition, unless they ran more tests. Surprisingly, I had done blood tests before that time for long-term disability insurance. The insurer had refused to insure me without explanation. Starting to be very sick, I did not pursue the work with them to understand their decision. Unfortunately, I learned a few weeks after my surgery that their test revealed the count of a certain type of protein was too high, therefore, too risky for them to insure me. They knew I was seriously sick but took about eight months to let me know. Had the insurer shared their results sooner, had doctors ran similar blood tests, or done a scan, I would have been diagnosed way sooner, which could have resulted in not needing chemotherapy.”

Incidence of Adenocarcinoma

Adenocarcinomas or malignant tumors of the duodenum are extremely rare, uncommon and difficult to manage and treat, according to Drs. P.L. Fagniez and N. Rotman in a book chapter in Surgical Treatment – Evidence-Based and Problem-Oriented, a medical textbook that assesses currently accepted clinical practice that takes into account when recommendations for patient treatment are made.The tumors represent 0.3 percent of gastrointestinal tract tumors and up to 50 percent of small bowel malignancies. They may arise from duodenal polyps or they may be associated with Celiac Disease. Five-year-survival varies widely according to published reports in the medical literature, but it is generally reported to be greater than 40 percent if the tumor is surgically removed. http://www.ncbi.nlm.nih.gov/books/NBK6953/.

Due to the low incidence of the disease globally, there is no randomized study comparing different types of treatment. In fact, the medical literature only discusses a small number of patients with this condition, who are usually older, or patients who are seen over a period of time. The treatment plan is complete surgical removal of the tumor, which is the only hope for a cure. Nonetheless, good long-term results have been observed with segmented tumor removal, particularly for tumors of the distal part of the duodenum, according to the same book chapter mentioned in the paragraph above.

A Bright Future Ahead

Nathalie believes in second chances and the value of waking up each and every day to new challenges and opportunities.

“Life is to be lived and enjoyed. I love what I do and I cherish my relationships, my work and my free time. In whatever I do, I give 100 percent.”

She believes she is very lucky to have had the diagnosis at this time of her life.

“In a way, my parents, my family, my husband were always present in my health journey. They followed up on doctors’ appointments, helped me with daily living chores, researched the medical literature, contacted new doctors, and generally, were my sounding board on everything. They were invaluable to me and it was my privilege that I am blessed with such a supportive family.

“I believe the road is set for you in life and it is up to all of us to seize the moment. My condition has given me strength to explore who I am and validate the way I always approach life.”

Nathalie Monette provided her permission to publish this interview on July 30, 2016.

 

Search Title:

Duodenum AND Cancer | Open Studies | Exclude Unknown in ClinicalTrials.gov Database. The search was conducted on July 30, 2016 and there were  45 studies found.

Presented, below, is a Subset of Clinical Trials on the List of 45 Studies related to Duodenum AND Cancer

https://clinicaltrials.gov/ct2/results?term=duodenum+AND+Cancer&recr=Open&no_unk=Y

SEE LINK, Below for the list of clinical trials currently recruiting:

Subset of Clinical Trials on the List of 45 Studies – Duodenum AND Cancer (6)

Or you may click on the following individual links below for clinical trials that are currently recruiting:

Spectroscopy From Duodenum

Condition:	Pancreatic Adenocarcinoma
Intervention:	Other: Spectroscopy device

A Randomized Trial of Two Surgical Techniques for Pancreaticojejunostomy in Patients Undergoing Pancreaticoduodenectomy

Conditions:	Pancreatic Neoplasms;   Biliary Tract Neoplasms;   Pancreatitis, Chronic;   Duodenal Neoplasms
Intervention:	Procedure: pancreaticojejunostomy

Endoscopic Characteristics of Duodenal and Ampullary Lesions

Condition:	Duodenal Diseases
Intervention:	Other: Tissue Sampling

EUS GUIDED Transduodenal Biopsy Using the 19G Flex

Condition:	Abdominal Neoplasms
Intervention:	Device: Expect™19Flex needle (Boston Scientific Corp.,Natick,MA,USA)

Study of Gastroduodenal Metallic Stent vs Gastrojejunostomy

Condition:	Gastric Cancer
Interventions:	Device: gastroduodenal stent placement;   Procedure: gastrojejunostomy

Prevalence of Small Bowel Polyps in Patients With Sporadic Duodenal Adenomas

Condition:	Polyps
Intervention:	Device: Small bowel video capsule endoscopy (VCE) GIVEN/COVIDIEN LTD

Long-term Outcomes of Endoscopic Resection (ER) of Lesions of the Duodenum and Ampulla

Condition:	Adenoma, Villous
Intervention:	Procedure: Endoscopic Mucosal Resection

Prophylactic Octreotide to Prevent Post Duodenal EMR and Ampullectomy Bleeding

Condition:	Adenoma
Interventions:	Drug: octreotide;   Other: No octreotide

 

The Use of a Restrictive Fluid Regimen With Hypertonic Saline for Patients Undergoing Pancreaticoduodenectomy

Condition:	Pancreaticoduodenectomy
Interventions:	Drug: 3% NaCl Solution;   Drug: Lactated Ringers Solution

Effects of Pancreaticoduodenectomy on Glucose Metabolism

Conditions:	Diabetes Mellitus;   Glucose Intolerance
Intervention:	—

 

 

REFERENCES/SOURCES

https://clinicaltrials.gov/ct2/results?term=duodenum+AND+Cancer&recr=Open&no_unk=Y

http://www.innerbody.com/image_dige02/dige21.html

Other related articles:

Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK6953/.

Other related articles were published in this Open Access Online Scientific Journal include the following:

 2016

LIVE 8:10 am – 11:20 am 4/27/2016 Combination Cancer Therapies: Drug Resistance and Therapeutic Index & Cancer Diagnostics: New Uses, New Reimbursements? & New Philanthropy: Patients Driving Innovation@2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

https://pharmaceuticalintelligence.com/2016/04/27/live-810-am-1120-am-4272016-combination-cancer-therapies-drug-resistance-and-therapeutic-index-cancer-diagnostics-new-uses-new-reimbursements-new-philanthropy-patients-driving-i/

Colon cancer and organoids

https://pharmaceuticalintelligence.com/2016/04/15/colon-cancer-and-organoids/

Checkpoint inhibitors for gastrointestinal cancers

https://pharmaceuticalintelligence.com/2016/02/14/checkpoint-inhibitors-for-gastrointestinal-cancers/

2015

Gluten-free Diets

https://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

Gastrointestinal Endocrinology

https://pharmaceuticalintelligence.com/2015/02/10/gastrointestinal-endocrinology/

 

 

 

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Marcela’s Story: A Liver Transplant Gives the Gift of Life

Posted in Cancer - General, Cancer and Current Therapeutics, Liver & Digestive Diseases Research, Patient Experience, Patient Experience: Personal Memories of Invasive Medical Intervantion, Patient Outlook, Patient’s Voice: Personal Experience with Invasive Medical Procedures, Uncategorized, tagged Cancer - General, Conditions and Diseases, liver, liver cancer, physician-patient relationship on July 23, 2016| Leave a Comment »

Marcela’s Story:  A Liver Transplant Gives the Gift of Life

Patient is HCV Positive, liver transplanted from a 22-year-old donor performed at age 70. Interview conducted 14 years post-liver transplant.

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

For Marcela Almada Calles of Valle de Bravo, Mexico, a picturesque town on the shores of Lake Avándaro about two hours outside of Mexico City where she has lived for 30 years, life is about seizing the moment and having “an open mind and positive attitude.”  An active woman in her 80’s, Marcela’s days are full of professional and personal achievements and a long list of activities still to accomplish. However, life wasn’t always so positive as she put her life on hold for two-and-a-half years to relocate to Los Angeles, California, so that she could have a liver transplant.

“My spirit and attitude have always been what has carried me through life and difficult situations. This time was no different.”

Image SOURCE: Photographs courtesy of Marcela Almada Calles.   

Marcela’s story started 20 years ago during a time when she operated a successful event planning and catering business for high-profile government and social dignitaries, pharmaceutical companies, and luxury department stores.

“I normally worked long hours from early morning until evening, until one day, I felt exceptionally tired and it became a huge effort to concentrate. My ankles were swollen and I was out of breath all the time and my skin was yellow. I felt sleepy and would sometimes become tired during the day. This was unusual for me. I knew something was not right.”

At that point, Marcela decided to make an appointment with her local physician and friend, Dr. Sergio Ulloa, a highly regarded rheumatologist and corporate and government affairs leader in Mexico, who examined her and took several blood tests. When the blood results came back, Dr. Ulloa immediately referred her to Dr. Sergio Kershenovich, a well-regarded hepatologist, at his private clinic, who checked her for symptoms of Hepatitis C. After that Marcela decided to get another opinion and went to see Dr. Fernando Quijano, a general surgeon, who immediately wanted her to have surgery because he had found a cancerous tumor in her liver.

“My doctors’ opinions were that I needed to have a liver transplant immediately because I was in liver failure. It appeared that I had a failing liver — and a tumor there as well and my liver was not working properly.”

Relocating Life to the United States

At that point, my six children – Marcela, Luis, Diego, Rodolfo, Gabriela, Mario — who live in parts of Mexico and Singapore became involved in my health care decisions and treatment plan.

“My son, Luis, believed the best treatment for me was to see a liver specialist in the United States so that I received the best care from a leading liver transplantation hospital. He made some connections with friends and that next day, Dr. Francisco Durazo, chief of Transplant Hepatology and medical director of the Dumont UCLA Liver Transplant Center in Los Angeles, told me to come immediately to see him. I remember my children were supportive and concerned, but were afraid for me as we all knew that I had a long road ahead of me.”

At that time, she was put on a national liver transplant list by the UCLA Transplant Center.

“What I didn’t know was that more than 9,000 potential recipients are currently awaiting liver transplants.”  http://transplants.ucla.edu/site.cfm?id=397

“Dr. Durazo was very concerned and told me that my liver was not working at all and I had to have a liver transplant as soon as possible, so he asked me to stay in Los Angeles, since I was now part of a transplant list.”

Evaluation By Transplant Team

Marcela’s case is no different than any other patient awaiting a liver transplant. According to their web site, the UCLA Transplant Center conducts evaluations over two or three days. During this time, the patients meets with a social worker, transplant hepatologist, surgeon, transplant coordinator, psychiatrist and dietitian, as well as other specialists as needed. The evaluation is customized to each patient’s medical condition. Once the evaluation is completed, each patient’s case is presented at a weekly meeting of the UCLA Liver Transplant Consultation Team. This group includes specialists from surgery, adult and pediatric hepatology, cardiology, pulmonary, nephrology, hematology, infectious disease, as well as transplant coordinators and social workers. At this time, the team determines if any other tests are required to ensure the patient’s candidacy for transplant, then the patient and the physician are notified of the recommendation made by the transplant team. http://transplants.ucla.edu/site.cfm?id=401

Waiting For Answers

Marcela arrived at UCLA in Los Angeles with her family on Mother’s Day — May 10, 1999 — for what she describes as “the best time in her life to be alive with the help of medicine and technology.” That meant that she needed to rent an apartment and live near the hospital in case the doctors received an anonymous donor who would give her the gift of life.

“I had to wear a beeper 24 hours a day and I was never alone. My children took turns over the next two-and-a-half years to give up their lives with their families to live with me and help me navigate the health care system and my upcoming surgery.”

Marcela filled her days at her new apartment in Los Angeles reading about her condition, meditating to quiet her mind, watching television, and talking with family, friends and neighbors.

“The doctors called me two times over the next few months, saying they had an anonymous liver donor and I needed to come now to the hospital for tests. Unfortunately, those blood tests and other diagnostic tests showed that I was not a good match, so the doctors sent me home. It was a frustrating time because I wanted to have the liver transplant surgery and move on with my life.”

Finally, after waiting eight months for a liver transplant, Marcela’s outlook on life was greatly improved when an anonymous donor gave her the gift of life – a new, healthy liver.

“The donor’s blood type was a match for me. The surgery took eight hours and it was successful. The doctors told me that my immune system might reject my new liver, so I was given a cocktail of medicines, such as anti-rejection drugs, corticosteroids, calcinurin inhibitors, mTOR inhibitors, and antibiotics and watched very closely in the hospital.”

Marcela was then permitted to leave the hospital only a week after her surgery.

“That was the happiest day of my life. My spirits were high and I had a life to live.”

Her children served as her strength.

“My children took turns flying back and forth to Los Angeles to stay with me. They had a long list of instructions from the doctor. I could take some walks and eat small meals for the next few weeks, but I couldn’t exert myself in any way. I developed a cold over the next few weeks, as my immune system was low, so I had to take special care to eat right, get enough sleep and, most of all, relax. My body, spirit and mind had much healing to do.”

For the next 1 ½ years, Los Angeles was my “second” home.

“I needed to remain there after the procedure so my doctors could monitor my progress. During that time, I felt stronger each day. The support of my family was a true blessing for me. They were my eyes and ears – and my greatest advocates. My doctor recommended that I come weekly for check-ups and go through a physical therapy program so that I could regain my liver function and physical strength. I followed all my doctor’s orders.”

Day by day, Marcela believed as if she could conquer the world.

“I decided, one day many months after the surgery, to become ‘irresponsible’ and spent time with a few good friends, Gabriela and Guadalupe, who traveled to see me. For a weekend, we went to Las Vegas to see shows and go to the casinos. I laughed, played and walked all I could. My children didn’t even know what I was up to, but I felt good and wanted to enjoy the world and my new freedom.”

Marcela was able to return home to Valle de Bravo with a fresh perspective, a long list of things to do, and many happy memories.

“Since that time, I have kept myself active and busy; I never let my mind and heart rest. I am also forever grateful to my anonymous liver donor because it is because of a 22-year-old young man who died in an unfortunate automobile accident that I am here today.”

Liver Transplant Facts

The liver is the body’s vital organ that you cannot live without. It serves many critical functions, including metabolism of drugs and toxins, removing degradation products of normal body metabolism and synthesis of many proteins and enzyme, which are necessary for blood to clot. Transplantation is the only cure for liver insufficiency or liver failure because no device or machine reliably performs all the functions of the liver. http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

According to a hospital transplant web site, overall, outcomes for liver transplantation are very good, but vary significantly depending on the indication for liver transplant as well as factors associated with the donor. Currently, the overall patient survival one year after liver transplant is 88 percent. Patient survival five years after liver transplant is 73 percent. These results vary significantly based on the indication for liver transplantation. The encouraging trend is that over the past 20 years short- and long-term patient survival has continued to improve. With advances in surgical technique, organ preservation, peri-operative care, and immunosuppression, survival will hopefully continue to improve in the future. http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

Life For Marcela Today

Science is helping rebalance medicine with the most innovative discoveries and new ways of treating illness.

“I am happy to be part of the solution with a happy ending, too.”

Today, Marcela leads a rich and full life.

“It’s been 14 years since my liver transplant. I continue to feel healthy and alive. Nothing will keep me from doing what I want to do.”

Marcela has an active social life. She takes frequent vacations around the world, including a three-month holiday to Asia, where she travels multiple times to Bali, Cambodia, China and Singapore, where her daughter lives. She is an avid golfer and organizes tournaments in many private golf courses. She is learning to speak French, which is an easy transition (she says) from speaking Spanish. She plays cards with a group of friends weekly, sings in a musical group, and takes dance lessons, too. Life is very, very good.

Editor’s note: We would like to thank Gabriela Contreras, a global communications consultant and patient advocate, for the tremendous help and support that she provided in locating and scheduling time to talk with Marcela Almada Calles.

Marcela Almada Calles provided her permission to publish this interview on July 21, 2016.

 

REFERENCE/SOURCE 

http://www.webmd.com/digestive-disorders/digestive-diseases-liver-transplantation

Other related articles:

Retrieved from http://transplants.ucla.edu/site.cfm?id=397

Retrieved from http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

Retrieved from http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

Other related articles were published in this Open Access Online Scientific Journal include the following: 

2016

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https://pharmaceuticalintelligence.com/2016/07/15/adoptive-t-cell-therapy-delivering-car-tcr-and-til-from-research-to-reality-chis-4th-annual-immuno-oncology-summit-september-1-2-2016-marriott-long-wharf-hotel-boston-ma/

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https://pharmaceuticalintelligence.com/2015/11/16/3-d-printed-liver/

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