Abstract CT228: Talazoparib (Tala) in patients (pts) with solid tumors with ATM alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Author: Hinshaw, Dominique C. ; Hall, Michael J. ; Gitau, Mark ; Schilsky, Richard L. ; Grantham, Gina N. ; Bivins, Dustin ; Calfa, Carmen J. ; Nazemzadeh, Reza ; Ganti, Apar K. ; Leonhardt, Lex ; Hafez, Navid ; Yan, Fengting ; DeRemer, David ; Gregory, Abigail ; Winer, Arthur ; Alese, Olatunji B. ; Outlaw, Darryl ; Dib, Elie G. ; Suhag, Vijay ; Mangat, Pam K. ; Garrett-Mayer, Elizabeth ; Halabi, Susan ; Pisick, Evan ; Rothe, Michael

AbstractBackground:TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with ATM mutation (mut) or deletion (del) treated with Tala are reported.Methods:Eligible pts had metastatic solid tumors, measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Low accruing histology-specific cohorts with ATM alterations were collapsed into 1 histology-pooled cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete or partial response (PR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR) and SD, and safety.Results:29 pts with nine different solid tumors with ATM mut (n=28) or del (n=1) were enrolled. 1 pt was not evaluable for efficacy. Table shows demographics, outcomes, and toxicity. 2 PR (lung and thyroid) and 10 SD16+ (pancreas [3], prostate [2], colon, breast, kidney, rectum, stomach, thyroid) were observed in pts with ATM mut for a DC rate of 41% (1-sided 90% CI, 29 to 100) and an OR rate of 7% (95% CI, 1 to 23). The null DC rate was rejected (p=0.0005). The pt with PR and lung cancer is still on tx and has exceeded 73 wks on study as of October 2024. 8 pts had ≥1 grade 3-4 tx-related adverse event (AE). No tx-related serious AE were reported.Conclusions:Tala met prespecified criteria to declare a signal of activity in pts with solid tumors with ATM mut.Citation Format:Elie G. Dib, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Dustin Bivins, Mark Gitau, Apar K. Ganti, Arthur Winer, Vijay Suhag, Darryl Outlaw, Michael J. Hall, Olatunji B. Alese, Reza Nazemzadeh, Evan Pisick, Fengting Yan, Navid Hafez, Carmen J. Calfa, Lex Leonhardt, David DeRemer, Abigail Gregory, Dominique C. Hinshaw, Gina N. Grantham, Susan Halabi, Richard L. Schilsky. Talazoparib (Tala) in patients (pts) with solid tumors with ATM alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT228.

05 Nov 2021·Blood

In silico Prediction Followed By I n Vitro validation Identifies a Survivin Inhibitor and an MCL-1 Inhibitor As a Potent Secondary Drug Against Refractory or Relapsed Mantle Cell Lymphoma

Author: Mukherjee, Ujjal Kumar ; Mitra, Amit Kumar ; Moore, Timothy ; Chakravarti, Sayak ; Mazumder, Suman

AbstractMantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm that develops from malignant B-lymphocytes in the outer edge or mantle zone of a lymph node. This is a sub-type of B-cell non-Hodgkin lymphoma characterized by rapid clinical progression and poor response rate to conventional chemotherapeutic drugs with recurrent relapse resulting in a short estimated 5-year overall survival (OS) of 2-5 years depending on the clinical risk. Combination therapies such as R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP constitute the front-line chemotherapeutic treatment landscape for MCL. Despite good initial response to the combination regimens, all patients develop resistance over time. The Bruton's tyrosine kinase inhibitor (BTKi) Ibrutinib and the proteasome inhibitor (PI) Bortezomib are FDA-approved therapies for refractory or relapsed (R/R) MCL with demonstrated high initial response rate in clinical trials. However, highly variable treatment response along with dose-limiting toxicities has limited the efficacy in real-world settings with the median progression-free survival (PFS) of <15 months and Over-al of 1-2 years.Thus, the identification of novel drugs that function either alone or as combination to curb the oncogenic progression as well as to reduce drug-associated toxicities is of high clinical significance.We have designed a novel optimization-regularization-based computational prediction algorithm called "secDrug" that uses large-scale pharmacogenomics databases like the GDSC1000 to identify novel secondary drugs for the management of treatment-resistant B-cell malignancies. We hypothesize that combination of our predicted secDrugs with BTKi/ PI will be useful in curbing oncogenic progressions of R/R MCL and abrogate drug resistance through simultaneous inhibition of multiple oncogenic factors/pathways. When applied to BTKi/PI-resistant R/R MCL, the top predicted secondary drugs (secDrugs) were YM155 (Survivin inhibitor) and S63845 (selective MCL-1 inhibitor). Interestingly, both Survivin and MCL-1 are reported to be over-expressed in MCL, and their expression is strongly correlated with the oncogenic progression and survivability of the patients.To validate our in-silico predictions, we performed in vitro cytotoxicity assays with the top predicted secDrugs (YM155 and S63845) as single agents (IC50 for YM155 4.87±0.66 nM, for S63845 0.9±1.1 uM) as well as in combination with BTKi/PI against a panel of MCL cell lines representing PI/BTKi sensitive, innate resistant (representing refractory MCL) and clonally-derived acquired resistant (representing relapsed MCL). Our results showed that the YM155 and S63845 exhibited significant synergistic cell killing activities (Combination index/ CI value of 0.31±0.49 as calculated using Chou-Talalay's CI theorem, C.I>1 depicts synergism) alone and in combination with Bortezomib (PI) and Ibrutinib (BTKi), especially in R/R MCL cell lines. Further, our results also showed that both YM155 and S63845 in combination with BTKi/PI were able to significantly lower the effective dose of both BTKi/PI required to achieve desired therapeutic response by >12 times (Dose Reduction Index or DRI for YM155 in combination is 15.87±4.93; DRI for S63845 in combination is 12.34±2.67), thereby making the cell lines relatively more BTKi/PI sensitive. Next, we performed next-generation RNA sequencing analysis to identify mechanisms of secDrug action and synergy. Our Gene expression profiling and Ingenuity pathway analysis of the RNAseq data among YM155-treated MCL cell lines revealed eIF4-p70S6K signaling and mTOR signaling as the top canonical pathways.Our study thus identified YM155 and S63845 as potential novel candidates for repurposing as secondary drugs in combination with BTKi/PI for the treatment of R/R MCL. Currently, we are exploring the probable subclonal molecular mechanisms governing the synergistic drug action by using single-cell transcriptomics analysis. As both YM155 and S63845 have reported activity against cancer stem-ness, we will further investigate the effect of our novel drugs on the cancer stem-like cells in MCL, which have a potential role in treatment resistance.The secDrug algorithm promises to serve as a universal prototype for the discovery of novel drug combination regimens for treatment outcomes in any cancer type by enhancing sensitivity or overcoming resistance to standard of care drugs.Figure 1 Figure 1.DisclosuresNo relevant conflicts of interest to declare.

16 Sep 2021·OncogeneQ1 · MEDICINE

Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors

Q1 · MEDICINE

Article

Author: Hu, Gangqing ; Loskutov, Juergen ; Maskey, Abha ; Pugacheva, Elena N ; Smolkin, Matthew B ; Gandhi, Jasleen ; Yanardag, Sila ; Chen, Dongquan ; Purazo, Marc L ; Margaryan, Naira V ; Voronkova, Maria A ; Choi, Hyeran ; Whately, Kristina M ; Wen, Sijin

Metastatic breast cancer causes most breast cancer-associated deaths, especially in triple negative breast cancers (TNBC). The metastatic drivers of TNBCs are still poorly understood, and effective treatment non-existent. Here we reveal that the presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia-Inducible Factor-1) signaling. Nuclear AURKA activates transcription of "hypoxia-induced genes" under normoxic conditions (pseudohypoxia) and without upregulation of oxygen-sensitive HIF1A subunit. We uncover that AURKA preferentially binds to HIF1B and co-localizes with the HIF complex on DNA. The mass-spectrometry analysis of the AURKA complex further confirmed the presence of CBP and p300 along with other TFIIB/RNApol II components. Importantly, the expression of multiple HIF-dependent genes induced by nuclear AURKA (N-AURKA), including migration/invasion, survival/death, and stemness, promote early cancer dissemination. These results indicate that nuclear, but not cytoplasmic, AURKA is a novel driver of early metastasis. Analysis of clinical tumor specimens revealed a correlation between N-AURKA presence and decreased patient survival. Our results establish a mechanistic link between two critical pathways in cancer metastasis, identifying nuclear AURKA as a crucial upstream regulator of the HIF1 transcription complex and a target for anti-metastatic therapy.

100 Deals associated with Uab Comprehensive Cancer Center

100 Translational Medicine associated with Uab Comprehensive Cancer Center

Corporation Tree

Boost your research with our corporation tree data.

view full example data

Pipeline

Pipeline Snapshot as of 10 May 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

Current Projects

Drug(Targets)	Indications	Global Highest Phase

Andrographolide	Prostatic Cancer More	Preclinical

Deal

Boost your decision using our deal data.

view full example data

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Profit

Explore the financial positions of over 360K organizations with Synapse.

view full example data

Grant & Funding(NIH)

Access more than 2 million grant and funding information to elevate your research journey.

view full example data

Investment

Gain insights on the latest company investments from start-ups to established corporations.

view full example data

Financing

Unearth financing trends to validate and advance investment opportunities.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis