Natalie Ngoi’s research while affiliated with University of Texas MD Anderson Cancer Center and other places

Background Transforming growth factor-beta 1 (TGFβ1) plays a crucial role in tumor progression and immunosuppression in cancer. SAR439459 is a second-generation monoclonal antibody that targets all TGFβ isoforms. A first-in-human study (NCT03192345) established the SAR439459 dose at 15 mg/kg every three weeks as the initial recommended phase 2 dose. Methods TACTIC (NCT04729725) is a phase Ib dose-expansion trial to evaluate the combination of SAR439459 (anti-TGF-β) and cemiplimab (anti-PD1) in pts with advanced solid tumors. Pts were mandated to have been treated with PD-1 or PD-L1 inhibitors (PD-1/L1i) as their most recent therapy. The primary objective of the trial was to assess efficacy; secondary objectives included toxicity; and translational studies included multiplex immunofluorescence (mIF) (n=2) and single-cell RNA-sequencing (5’GEX) of tumor (n=1) and blood (n=3). Results Three pts were enrolled: advanced clear cell renal cell carcinoma (ccRCC), high-grade pancreatic neuroendocrine carcinoma (NEC), and castration-resistant prostate cancer (CRPC) (n=1 each). The ccRCC pt achieved a confirmed RECISTv1.1 partial response (PR), with -55% reduction in target lesions, progression-free survival (PFS) of 12 mths, and overall survival (OS) of 26 mths. The other two pts had RECISTv1.1 progressive disease (PD) Hemorrhagic adverse events occurred in all pts. Two grade 3 treatment-related adverse events were reported: rash and retroperitoneal hemorrhage. Two pts (ccRCC and CRPC pts) developed skin squamous cell carcinomas, attributed to SAR439459 and were treated with resection. Single-cell sequencing revealed higher Treg activation as well as CD8+ T cell (LAG3, TIGIT) and CD4+ T cell (TIGIT, PDCD1, CTLA4) exhaustion profiles in the blood samples collected at C2D1 (post SAR439459, pre-cemiplimab) of both pts who had PD versus the pt with the PR. LAG3 and TIGIT were also present in CD8+ T cells from on-treatment biopsies collected from one of the pts with PD. A unique on-treatment CD4+ T cell signature associated with NK-kB activation in response to TNF was found in the circulation of the pt with PR. Within the tumor microenvironment, longitudinal mIF analysis of one of the pts with PD demonstrated reductions in TGF-β, pSMAD3 and immune infiltrate by C2D1. Conclusions In this phase 1b study, SAR439459 and cemiplimab demonstrated a deep and durable RECISTv1.1 PR in a post-PD-1/L1i treated pt with advanced ccRCC. While translational data are limited, these findings support the association of systemic immune activation with response to therapy. Despite this, based on data from another study (NCT03192345), all investigations of SAR439459 were discontinued due to lack of sufficient antitumor activity and the associated bleeding risk. Citation Format Carlos Torrado, Katarzyna Tomczak, Ecaterina E. Dumbrava, Baohua Sun, Natalie Ngoi, Claudio Arrechedera, Edwin R. Parra, Jordi Rodon Anhert, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Siqing Fu, Aung Naing, Paula R. Pohlmann, David S. Hong, Funda Meric-Bernstam, Pavlos Msaouel, Cara L. Haymaker, Timothy A. Yap. Clinical and translational study of the TGF-β monoclonal antibody SAR439459 in combination with the PD-1 inhibitor cemiplimab for patients (pts) with advanced solid tumors: Results from the phase 1b TACTIC trial [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 CT046.

Introduction Over the past 20 years, advances in precision oncology and cancer genetics have identified numerous actionable oncogenic drivers, leading to new drug development and clinical application. However, tumor cells can adapt and develop resistance mechanisms (MoR), and the mechanisms of action (MoA) of these drugs are only partially understood, highlighting the need for research focused on both MoR and MoA. Following the success of the MATCH-R clinical trial (NCT02517892, 2015-2022), the UNLOCK program was launched in 2022 to better understand the MoA and MoR of innovative drugs (phase 1 to approval) through integrated clinical and translational research. As part of this initiative, we developed preclinical models, including PDX models from patients who developed resistance, to support the development of new therapeutic strategies. Methods Fresh tumor biopsy specimens were prospectively collected from patients through the MATCH-R clinical trial (NCT02517892) or the UNLOCK program. PDX models were established in NOD Scid Gamma (NSG) mice, which were then developed and characterized. These models underwent immunohistochemistry, comprehensive molecular profiling (including whole exome sequencing [WES] and bulk RNA sequencing [RNA-seq]), and pharmacological validation. Results As of November 2024, 197 PDX models have been successfully generated from 519 biopsies, with a global take rate of 38%. These models are developed across several cohorts, including castration-resistant prostate cancer (22 PDX: 18 AR pathway inhibitors, 1 post-PARPi, and 3 Lu-PSMA), lung cancer (40 PDX with EGFR inhibitors, including 28 post-osimertinib, and 22 PDX with ALK inhibitors, including 2 post-brigatinib, 9 post-lorlatinib, and 6 post-alectinib). Additionally, 34 PDX models have been developed for the FGFR cohorts with FGFR2/FGFR3 alterations across various cancers, including cholangiocarcinomas, bladder carcinomas, gynecological carcinomas, and pancreatic cancers. We also developed 32 PDX models with KRAS mutations (G12C, n=23; G12D, n=9) from various tumors, including lung, pancreatic, gynecological, and colon cancers. Recently, we launched a new UNLOCK cohort focused on antibody-drug conjugate therapy, developing 12 additional PDX models. These PDX models faithfully replicate the genetic, transcriptional, phenotypic, and pharmacologic features of the original biopsies, providing a unique preclinical platform for testing novel drugs and combination therapies. Adaptive treatments with new or combinatorial strategies are being explored to restore drug sensitivity. Conclusion The development of 197 PDX models under the UNLOCK program represents a significant resource, enabling the evaluation of novel drugs, adaptive treatment strategies, and combinatorial approaches. This unique collection of PDX models paves the way for advancing precision oncology and overcoming therapeutic resistance. Citation Format Ludovic Bigot, Nobre Nobre, Alice Da silva, Melissandre Meteau, Mathis Delavigne, Miguel Soares, Francesco Facchinetti, Loic Poiraudeau, Floriane Braye, Inmaculada Inmaculada Alonso Garcia, Natalie Ngoi, Alexandre Halimi, Emlie Natali, Damien Vasseur, Kristi Beshiri, Claudio Claudio Nicotra, Maud Ngo-Camus, Lambros Tselikas, Beatriz Beatriz Alonso de Castro, Julieta Rodriguez, Maria Fernanda Mosele, Maud Kamal, Gérôme Jules-Clement, Karim Fizazi, Christophe Massard, Benjamin BESSE, Luc Friboulet, Yohann Loriot. UNLOCK, a preclinical platform of PDX models resistant to innovative therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1276.

Synthetic lethality is a genetic phenomenon whereby the simultaneous presence of two different genetic alterations impairs cellular viability. Importantly, targeting synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be considered undruggable. High-throughput screening methods based on modern CRISPR-Cas9 technologies have emerged and become crucial for identifying novel synthetic lethal interactions with the potential for translation into biologically rational cancer therapeutic strategies as well as associated predictive biomarkers of response capable of guiding patient selection. Spurred by the clinical success of PARP inhibitors in patients with BRCA-mutant cancers, novel agents targeting multiple synthetic lethal interactions within DNA damage response pathways are in clinical development, and rational strategies targeting synthetic lethal interactions spanning alterations in epigenetic, metabolic and proliferative pathways have also emerged and are in late preclinical and/or early clinical testing. In this Review, we provide a comprehensive overview of established and emerging technologies for synthetic lethal drug discovery and development and discuss promising therapeutic strategies targeting such interactions.

Purpose Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy. Methods The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0–1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 min prior to and continuing up to 90 min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0–2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy. Results Eighty-three patients were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation. Conclusion SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls.

Introduction Germline genetic testing (GT) is recommended for all women with EOC but universal GT is hampered by limited resources. Decentralized GT by non-geneticists can potentially improve access. Methods A decentralized clinic run by gynecologists who underwent training with the Cancer Genetics Service, was introduced at the National University Hospital. Patients with newly diagnosed EOC were referred for counselling. We studied the uptake of GT. Results Between April 2021 to December 2023, 88 EOC patients were seen (median waiting time from referral 45 days vs historical 90 days; p<0.01). Majority were Chinese (67.0%), median age at diagnosis 58.5 years, 54/88 (61.4%) had FIGO III/IV disease, most common subtype being high grade serous (60.2%). 26.1% had a family history of breast and/or ovarian cancers. 50/88 (56.8%) underwent GT. 12/50 (24.0%) were found to have pathogenic variants (PV), 54.0% tested negative, while 22.0% had variants of uncertain significance. 10/12 PV were in homologous recombination deficiency (HRD)-associated genes: BRCA1 (3), BRCA2 (2), RAD51C (2), RAD51D (3). 29/50 (58.0%) had concurrent somatic testing, with 58.6% concordant (24.1% HRD on both; 34.5% negative on both). 41.4% had HRD only on somatic testing, confirming no need for cascade testing. GT informed treatment for 3 patients with BRCA1/2 PV who declined somatic testing and revealed unexpected PV in 2 patients (MSH2 and TP53) necessitating further risk management. Conclusion/Implications Decentralization of germline GT for patients with EOC by gynecologists is associated with acceptable uptake and improved waiting time. Timely GT can optimize management and facilitate familial risk assessment.

Clear cell carcinomas arising from the gynecological tract (including from the ovary, endometrium, cervix, vulva or vagina) represent rare but clinically significant entities with intriguing overlapping characteristics. Epidemiologically, clear cell carcinomas exhibit a predilection for women of Asian ethnicity and are often associated with a previous or synchronous diagnosis of endometriosis. Pathologically, despite originating from different primary organs, clear cell carcinomas of the gynecological tract show a similar morphological and immunophenotypic features on traditional histopathology, such as the expression of Napsin A and HNF1b on immunohistochemistry, without the expression of WT1. Well-described molecular characteristics of these cancers include recurrent mutations in genes such as ARID1A, PIK3CA, and/or PTEN, although significant variations exist across the different anatomical sites. Therapeutically, optimal management remains challenging due to the relative rarity of clear cell carcinomas and limited subtype-specific clinical trials. Surgery remains the cornerstone of treatment, often complemented by systemic chemotherapy. However, promising drugs targeting angiogenesis or the immune microenvironment have emerged in recent years, leading to clinical successes and are likely to reshape the therapeutic landscape of gynecological clear cell carcinoma. This review summarizes the commonalities and disparities in terms of epidemiology, pathology, molecular features and therapeutic approach, amongst clear cell carcinomas of different anatomical origin, offering a foundation for further research and dedicated therapeutic interventions for these malignancies.