bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table S1 from FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma
Authors: Maguire William F. , Lee Daniel , Weinstock Chana , Gao Xin , Bulik Catharine C. , Agrawal Sundeep , Chang Elaine , Hamed Salaheldin S. , Bloomquist Erik W. , Tang Shenghui , Pazdur Richard , Kluetz Paul G. , Amiri-Kordestani Laleh , Suzman Daniel L.
Published: May 2024

Table S1 shows selected laboratory abnormalities ≥ 20 % (All Grades) in EV-103
Supplemental Table 6 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas
Authors: Desai Pankaj B. , Karve Aniruddha S. , Zawit Misam , Arora Priyanka , Dave Nimita , Awosika Joy , Li Ningjing , Fuhrman Bethany , Medvedovic Mario , Sallans Larry , Kendler Ady , DasGupta Biplab , Plas David , Curry Richard , Zuccarello Mario , Chaudhary Rekha , Sengupta Soma , Wise-Draper Trisha M.
Published: May 2024

Supplemental Table 6: List of GO differentially expressed genes
Supplementary Figure S1 from FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma
Authors: Maguire William F. , Lee Daniel , Weinstock Chana , Gao Xin , Bulik Catharine C. , Agrawal Sundeep , Chang Elaine , Hamed Salaheldin S. , Bloomquist Erik W. , Tang Shenghui , Pazdur Richard , Kluetz Paul G. , Amiri-Kordestani Laleh , Suzman Daniel L.
Published: May 2024

Figure S1 is a schematic diagram of key datasets supporting the FDA’s efficacy review for accelerated approval of enfortumab vedotin plus pembrolizumab for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer
Supplemental Figure 2 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas
Authors: Desai Pankaj B. , Karve Aniruddha S. , Zawit Misam , Arora Priyanka , Dave Nimita , Awosika Joy , Li Ningjing , Fuhrman Bethany , Medvedovic Mario , Sallans Larry , Kendler Ady , DasGupta Biplab , Plas David , Curry Richard , Zuccarello Mario , Chaudhary Rekha , Sengupta Soma , Wise-Draper Trisha M.
Published: May 2024

Supplemental Figure 2: Gender-based comparison of Tumoral LTZ and E2 concentrations across the five-dose cohorts
Supplementary Table S1 from A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Kim Chang Gon , Hong Min Hee , Kim Dahee , Lee Brian Hyohyoung , Kim Hyunwook , Ock Chan-Young , Kelly Geoffrey , Bang Yoon Ji , Kim Gamin , Lee Jung Eun , Kim Chaeyeon , Kim Se-Heon , Hong Hyun Jun , Park Young Min , Sim Nam Suk , Park Heejung , Park Jin Woo , Lee Chang Geol , Kim Kyung Hwan , Park Goeun , Jung Inkyung , Han Dawoon , Kim Jong Hoon , Cha Junha , Lee Insuk , Kang Mingu , Song Heon , Oum Chiyoon , Kim Seulki , Kim Sukjun , Lim Yoojoo , Kim-Schulze Seunghee , Merad Miriam , Yoon Sun Och , Kim Hyun Je , Koh Yoon Woo , Kim Hye Ryun
Published: May 2024

List of antibodies.
Supplementary Figure S4 from First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors
Authors: Yap Timothy A. , Tolcher Anthony W. , Plummer Ruth , Mukker Jatinder Kaur , Enderlin Marta , Hicking Christine , Grombacher Thomas , Locatelli Giuseppe , Szucs Zoltan , Gounaris Ioannis , de Bono Johann S.
Published: May 2024

Figure S4. Tuvusertib PK/PD relationship.
Supplementary Figure S2 from First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors
Authors: Yap Timothy A. , Tolcher Anthony W. , Plummer Ruth , Mukker Jatinder Kaur , Enderlin Marta , Hicking Christine , Grombacher Thomas , Locatelli Giuseppe , Szucs Zoltan , Gounaris Ioannis , de Bono Johann S.
Published: May 2024

Figure S2. Change from baseline in tumor size and tuvusertib dose levels (FAS/SAF Analysis Set)
Supplementary Figure S1 from First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors
Authors: Yap Timothy A. , Tolcher Anthony W. , Plummer Ruth , Mukker Jatinder Kaur , Enderlin Marta , Hicking Christine , Grombacher Thomas , Locatelli Giuseppe , Szucs Zoltan , Gounaris Ioannis , de Bono Johann S.
Published: May 2024

Figure S1. Tuvusertib in vivo activity in ATM- and ARID1A-mutated xenograft models in mice
Supplementary Figure S20 from A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Kim Chang Gon , Hong Min Hee , Kim Dahee , Lee Brian Hyohyoung , Kim Hyunwook , Ock Chan-Young , Kelly Geoffrey , Bang Yoon Ji , Kim Gamin , Lee Jung Eun , Kim Chaeyeon , Kim Se-Heon , Hong Hyun Jun , Park Young Min , Sim Nam Suk , Park Heejung , Park Jin Woo , Lee Chang Geol , Kim Kyung Hwan , Park Goeun , Jung Inkyung , Han Dawoon , Kim Jong Hoon , Cha Junha , Lee Insuk , Kang Mingu , Song Heon , Oum Chiyoon , Kim Seulki , Kim Sukjun , Lim Yoojoo , Kim-Schulze Seunghee , Merad Miriam , Yoon Sun Och , Kim Hyun Je , Koh Yoon Woo , Kim Hye Ryun
Published: May 2024

Case studies of nodal immune flares after neoadjuvant durvalumab (A) and durvalumab+tremelimumab (B) therapy.
Supplementary Table S8 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Table 8. Patients with positive antibodies against CART at some point that remain in response after a long follow-up (cohort 1).
Supplementary Figure S18 from A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Kim Chang Gon , Hong Min Hee , Kim Dahee , Lee Brian Hyohyoung , Kim Hyunwook , Ock Chan-Young , Kelly Geoffrey , Bang Yoon Ji , Kim Gamin , Lee Jung Eun , Kim Chaeyeon , Kim Se-Heon , Hong Hyun Jun , Park Young Min , Sim Nam Suk , Park Heejung , Park Jin Woo , Lee Chang Geol , Kim Kyung Hwan , Park Goeun , Jung Inkyung , Han Dawoon , Kim Jong Hoon , Cha Junha , Lee Insuk , Kang Mingu , Song Heon , Oum Chiyoon , Kim Seulki , Kim Sukjun , Lim Yoojoo , Kim-Schulze Seunghee , Merad Miriam , Yoon Sun Och , Kim Hyun Je , Koh Yoon Woo , Kim Hye Ryun
Published: May 2024

High-dimensional profiling of regulatory CD4+ T cells.
Supplementary Figure S17 from A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Kim Chang Gon , Hong Min Hee , Kim Dahee , Lee Brian Hyohyoung , Kim Hyunwook , Ock Chan-Young , Kelly Geoffrey , Bang Yoon Ji , Kim Gamin , Lee Jung Eun , Kim Chaeyeon , Kim Se-Heon , Hong Hyun Jun , Park Young Min , Sim Nam Suk , Park Heejung , Park Jin Woo , Lee Chang Geol , Kim Kyung Hwan , Park Goeun , Jung Inkyung , Han Dawoon , Kim Jong Hoon , Cha Junha , Lee Insuk , Kang Mingu , Song Heon , Oum Chiyoon , Kim Seulki , Kim Sukjun , Lim Yoojoo , Kim-Schulze Seunghee , Merad Miriam , Yoon Sun Och , Kim Hyun Je , Koh Yoon Woo , Kim Hye Ryun
Published: May 2024

Dynamic changes in the composition of non-regulatory CD4+ T cells in response to the treatment administered.
Supplementary Table S5 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Table 5. Cox regression analysis of the impact of the levels of cytokines in progressionfree (PFS) and overall survival (OS).
Supplementary Table S2 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Table 2. Patients diagnosed with a neoplasia.
Supplementary Table S1 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Table 1. Representativeness of Study Participants.
Supplementary Figure S12 from A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Kim Chang Gon , Hong Min Hee , Kim Dahee , Lee Brian Hyohyoung , Kim Hyunwook , Ock Chan-Young , Kelly Geoffrey , Bang Yoon Ji , Kim Gamin , Lee Jung Eun , Kim Chaeyeon , Kim Se-Heon , Hong Hyun Jun , Park Young Min , Sim Nam Suk , Park Heejung , Park Jin Woo , Lee Chang Geol , Kim Kyung Hwan , Park Goeun , Jung Inkyung , Han Dawoon , Kim Jong Hoon , Cha Junha , Lee Insuk , Kang Mingu , Song Heon , Oum Chiyoon , Kim Seulki , Kim Sukjun , Lim Yoojoo , Kim-Schulze Seunghee , Merad Miriam , Yoon Sun Och , Kim Hyun Je , Koh Yoon Woo , Kim Hye Ryun
Published: May 2024

Dynamic changes in the composition of major immune cell types in response to the treatment administered.
Supplementary Figure S7 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Figure 7. Persistence of ARI0002h in the peripheral blood according to prior drug refractoriness and allogeneic stem cell transplantation
Supplementary Video S2 from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer
Authors: Hedayat Somaieh , Cascione Luciano , Cunningham David , Schirripa Marta , Lampis Andrea , Hahne Jens C. , Tunariu Nina , Hong Sung Pil , Marchetti Silvia , Khan Khurum , Fontana Elisa , Angerilli Valentina , Delrieux Mia , Nava Rodrigues Daniel , Procaccio Letizia , Rao Sheela , Watkins David , Starling Naureen , Chau Ian , Braconi Chiara , Fotiadis Nicos , Begum Ruwaida , Guppy Naomy , Howell Louise , Valenti Melanie , Cribbes Scott , Kolozsvari Bernadett , Kirkin Vladimir , Lonardi Sara , Ghidini Michele , Passalacqua Rodolfo , Elghadi Raghad , Magnani Luca , Pinato David J. , Di Maggio Federica , Ghelardi Filippo , Sottotetti Elisa , Vetere Guglielmo , Ciracì Paolo , Vlachogiannis Georgios , Pietrantonio Filippo , Cremolini Chiara , Cortellini Alessio , Loupakis Fotios , Fassan Matteo , Valeri Nicola
Published: May 2024

1021PD co-culture
Supplementary Figure S5 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Figure 5. ARI0002h persistence according to baseline tumor burden measured as proportion of bone marrow plasma cells and soluble BCMA.
Supplementary Figure S3 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Figure 3. Persistence of ARI0002h in the peripheral blood at each timepoint.
Supplementary Methods S1 from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer
Authors: Hedayat Somaieh , Cascione Luciano , Cunningham David , Schirripa Marta , Lampis Andrea , Hahne Jens C. , Tunariu Nina , Hong Sung Pil , Marchetti Silvia , Khan Khurum , Fontana Elisa , Angerilli Valentina , Delrieux Mia , Nava Rodrigues Daniel , Procaccio Letizia , Rao Sheela , Watkins David , Starling Naureen , Chau Ian , Braconi Chiara , Fotiadis Nicos , Begum Ruwaida , Guppy Naomy , Howell Louise , Valenti Melanie , Cribbes Scott , Kolozsvari Bernadett , Kirkin Vladimir , Lonardi Sara , Ghidini Michele , Passalacqua Rodolfo , Elghadi Raghad , Magnani Luca , Pinato David J. , Di Maggio Federica , Ghelardi Filippo , Sottotetti Elisa , Vetere Guglielmo , Ciracì Paolo , Vlachogiannis Georgios , Pietrantonio Filippo , Cremolini Chiara , Cortellini Alessio , Loupakis Fotios , Fassan Matteo , Valeri Nicola
Published: May 2024

List of Reagents
Supplementary Figure S13 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Figure 13. Progression-free survival according to triple-refractoriness, high-risk cytogenetics, extramedullary involvement and ISS.
Supplementary Figure S5 from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer
Authors: Hedayat Somaieh , Cascione Luciano , Cunningham David , Schirripa Marta , Lampis Andrea , Hahne Jens C. , Tunariu Nina , Hong Sung Pil , Marchetti Silvia , Khan Khurum , Fontana Elisa , Angerilli Valentina , Delrieux Mia , Nava Rodrigues Daniel , Procaccio Letizia , Rao Sheela , Watkins David , Starling Naureen , Chau Ian , Braconi Chiara , Fotiadis Nicos , Begum Ruwaida , Guppy Naomy , Howell Louise , Valenti Melanie , Cribbes Scott , Kolozsvari Bernadett , Kirkin Vladimir , Lonardi Sara , Ghidini Michele , Passalacqua Rodolfo , Elghadi Raghad , Magnani Luca , Pinato David J. , Di Maggio Federica , Ghelardi Filippo , Sottotetti Elisa , Vetere Guglielmo , Ciracì Paolo , Vlachogiannis Georgios , Pietrantonio Filippo , Cremolini Chiara , Cortellini Alessio , Loupakis Fotios , Fassan Matteo , Valeri Nicola
Published: May 2024

Supplementary Figure S5. Ex vivo co-cultures
Supplementary Figure S10 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Figure 10. Progression-free and overall survival according to cytokine values
Supplementary Data S1 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Oliver-Caldes Aina , Español-Rego Marta , Zabaleta Aintzane , González-Calle Verónica , Navarro-Velázquez Sergio , Inogés Susana , de Cerio Ascensión López-Díaz , Cabañas Valentín , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Moreno David F. , Martínez-Cibrian Nuria , López-Corral Lucía , Pérez-Amill Lorena , Martin-Antonio Beatriz , Rosiñol Laura , Cid Joan , Tovar Natalia , Sáez-Peñataro Joaquín , López-Parra Miriam , Olesti Eulalia , Guillén Elena , Varea Sara , Rodríguez-Lobato Luis Gerardo , Battram Anthony M. , González Marta Sonia , Sánchez-Salinas Andrés , González-Navarro Azucena , Ortiz-Maldonado Valentín , Delgado Julio , Prósper Felipe , Juan Manel , Martínez-López Joaquín , Moraleda José M. , Mateos Maria Victoria , Urbano-Ispizua Álvaro , Paiva Bruno , Pascal Mariona , Fernández de Larrea Carlos
Published: May 2024

Summary of the Study Protocol
Supplementary Table S4 from Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series
Authors: Anselmino Nicolas , Labanca Estefania , Shepherd Peter D.A. , Dong Jiabin , Yang Jun , Song Xiaofei , Nandakumar Subhiksha , Kundra Ritika , Lee Cindy , Schultz Nikolaus , Zhang Jianhua , Araujo John C. , Aparicio Ana M. , Subudhi Sumit K. , Corn Paul G. , Pisters Louis L. , Ward John F. , Davis John W. , Vazquez Elba S. , Gueron Geraldine , Logothetis Christopher J. , Futreal Andrew , Troncoso Patricia , Chen Yu , Navone Nora M.
Published: May 2024

Fusions identified in MDA PCa PDX cohort
Data from Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia
Authors: Modak Rucha V. , de Oliveira Rebola Katia G. , McClatchy John , Mohammadhosseini Mona , Damnernsawad Alisa , Kurtz Stephen E. , Eide Christopher A. , Wu Guanming , Laderas Ted , Nechiporuk Tamilla , Gritsenko Marina A. , Hansen Joshua R. , Hutchinson Chelsea , Gosline Sara J.C. , Piehowski Paul , Bottomly Daniel , Short Nicholas , Rodland Karin , McWeeney Shannon K. , Tyner Jeffrey W. , Agarwal Anupriya
Published: May 2024

AbstractPurpose:
Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML.
Experimental Design:
We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors (MEKi). We validated this association through loss-of-function and pharmacologic inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML.
Results:
Our multifaceted analysis unveiled that CCL2 activates multiple prosurvival pathways, including MAPK and cell-cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacologic inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance.
Conclusions:
Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.
Data from Molecular Profiling and the Impact of Treatment on Outcomes in Adenoid Cystic Carcinoma Type I and II
Authors: Hanna Glenn J. , Grover Punita , Elliott Andrew , McGrath Julie , Xiu Joanne , Sukari Ammar , Johnson Jennifer M. , Wise-Draper Trisha
Published: May 2024

AbstractPurpose:
Adenoid cystic carcinoma (ACC) is an uncommon salivary gland cancer with no approved therapies available to treat advanced, incurable disease. Recent molecular profiling efforts have identified two important subtypes: the more aggressive ACC-I is characterized by Notch pathway alterations and MYC amplification whereas ACC-II demonstrates a more indolent phenotype and TP63 overexpression.
Experimental Design:
This retrospective observational cohort study involved de-identified samples from 438 patients with ACC with tumor samples sent for commercially-available molecular profiling (Caris Life Sciences). Next-generation whole-exome and whole-transcriptomic sequencing was performed on primary and metastatic samples. Immunostaining for PD-L1 and RNA deconvolution (quanTIseq) was used to explore the tumor immune microenvironment (TME). Real-world clinical and survival outcome metrics were extracted from insurance claims data.
Results:
MYC expression was 1.61-fold higher (39.8 vs. 24.7; P < 0.0001) among NOTCH1-mutant ACC-I tumors, whereas MYB/L1 fusion rates were similar among ACC-I/II. The median B-cell fraction in the TME was higher among ACC-II (7.1% vs. 5.8%; P < 0.01), although infiltrating T cells subsets were low among either ACC subgroup (both <1%). When pooling systemic treatment categories, ACC-I patients had worse outcomes with available therapies (HR, 3.06; 95% confidence interval, 1.65–5.68; P < 0.01), with no significant difference in overall survival between ACC-I/II based on chemotherapy or VEGFR tyrosine kinase inhibitor exposure in smaller subsets.
Conclusions:
We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and -II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.
Data from Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma
Authors: Schreck Karisa C. , Strowd Roy E. , Nabors Louis B. , Ellingson Benjamin M. , Chang Michael , Tan Sze K. , Abdullaev Zied , Turakulov Rust , Aldape Kenneth , Danda Neeraja , Desideri Serena , Fisher Joy , Iacoboni Michaella , Surakus Trisha , Rudek Michelle A. , Bettegowda Chetan , Grossman Stuart A. , Ye Xiaobu
Published: May 2024

AbstractPurpose:
Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600–mutated HGG.
Patients and Methods:
In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy.
Results:
Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected.
Conclusions:
Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.
Data from FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma
Authors: Maguire William F. , Lee Daniel , Weinstock Chana , Gao Xin , Bulik Catharine C. , Agrawal Sundeep , Chang Elaine , Hamed Salaheldin S. , Bloomquist Erik W. , Tang Shenghui , Pazdur Richard , Kluetz Paul G. , Amiri-Kordestani Laleh , Suzman Daniel L.
Published: May 2024

Abstract
On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59–76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.
Data from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas
Authors: Desai Pankaj B. , Karve Aniruddha S. , Zawit Misam , Arora Priyanka , Dave Nimita , Awosika Joy , Li Ningjing , Fuhrman Bethany , Medvedovic Mario , Sallans Larry , Kendler Ady , DasGupta Biplab , Plas David , Curry Richard , Zuccarello Mario , Chaudhary Rekha , Sengupta Soma , Wise-Draper Trisha M.
Published: May 2024

AbstractPurpose:
High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs.
Patients and Methods:
We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) >2 μmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0.
Results:
Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 μmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis.
Conclusions:
On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.
Data from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer
Authors: Hedayat Somaieh , Cascione Luciano , Cunningham David , Schirripa Marta , Lampis Andrea , Hahne Jens C. , Tunariu Nina , Hong Sung Pil , Marchetti Silvia , Khan Khurum , Fontana Elisa , Angerilli Valentina , Delrieux Mia , Nava Rodrigues Daniel , Procaccio Letizia , Rao Sheela , Watkins David , Starling Naureen , Chau Ian , Braconi Chiara , Fotiadis Nicos , Begum Ruwaida , Guppy Naomy , Howell Louise , Valenti Melanie , Cribbes Scott , Kolozsvari Bernadett , Kirkin Vladimir , Lonardi Sara , Ghidini Michele , Passalacqua Rodolfo , Elghadi Raghad , Magnani Luca , Pinato David J. , Di Maggio Federica , Ghelardi Filippo , Sottotetti Elisa , Vetere Guglielmo , Ciracì Paolo , Vlachogiannis Georgios , Pietrantonio Filippo , Cremolini Chiara , Cortellini Alessio , Loupakis Fotios , Fassan Matteo , Valeri Nicola
Published: May 2024

AbstractPurpose:
The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice.
Experimental Design:
Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses.
Results:
Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652–3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a “control” group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652–3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option.
Conclusions:
Our results identify MIR652–3p as a potential biomarker and as a driver of cell and non–cell-autonomous mechanisms of resistance to regorafenib.
Data from Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series
Authors: Anselmino Nicolas , Labanca Estefania , Shepherd Peter D.A. , Dong Jiabin , Yang Jun , Song Xiaofei , Nandakumar Subhiksha , Kundra Ritika , Lee Cindy , Schultz Nikolaus , Zhang Jianhua , Araujo John C. , Aparicio Ana M. , Subudhi Sumit K. , Corn Paul G. , Pisters Louis L. , Ward John F. , Davis John W. , Vazquez Elba S. , Gueron Geraldine , Logothetis Christopher J. , Futreal Andrew , Troncoso Patricia , Chen Yu , Navone Nora M.
Published: May 2024

AbstractPurpose:
Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.
Experimental Design:
We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy.
Results:
The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response–associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets.
Conclusions:
We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.
Arming Vδ2 T Cells with Chimeric Antigen Receptors to Combat Cancer
Authors: Thomas Pauline , Paris Pierre , Pecqueur Claire
Published: May 2024

Immunotherapy has emerged as a promising approach in the field of cancer treatment, with chimeric antigen receptor (CAR) T-cell therapy demonstrating remarkable success. However, challenges such as tumor antigen heterogeneity, immune evasion, and the limited persistence of CAR-T cells have prompted the exploration of alternative cell types for CAR-based strategies. Gamma delta T cells, a unique subset of lymphocytes with inherent tumor recognition capabilities and versatile immune functions, have garnered increasing attention in recent years. In this review, we present how arming Vδ2-T cells might be the basis for next-generation immunotherapies against solid tumors. Following a comprehensive overview of γδ T-cell biology and innovative CAR engineering strategies, we discuss the clinical potential of Vδ2 CAR-T cells in overcoming the current limitations of immunotherapy in solid tumors. Although the applications of Vδ2 CAR-T cells in cancer research are relatively in their infancy and many challenges are yet to be identified, Vδ2 CAR-T cells represent a promising breakthrough in cancer immunotherapy.
FIGURE 4 from Mutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer
Authors: Wang Ruizhong , Khatpe Aditi S. , Kumar Brijesh , Mang Henry Elmer , Batic Katie , Adebayo Adedeji K. , Nakshatri Harikrishna
Published: May 2024

Tumors derived from breast epithelial cells transformed with HRASG12V oncogene cause significant skeletal muscle defects. A, Metastatic breast cancers show significant genomic aberrations in four RAS proto-oncogenes. B, Growth rate of tumors derived from three cell lines—TKTB34-RAS, TKTB6-RAS, and TKTB34-PIK3CA. A total of 1 × 106 cells were injected to the mammary fat pad. C, RAS protein levels in transformed cell lines. D, Impaired rotarod performance were observed in mice bearing tumors from RAS transformed cells. E, Mutant RAS oncogene-derived tumors but not mutant PIK3CA-derived tumors caused reduction in skeletal muscle contraction force. F, Tumors derived from TKTB34-RAS, which expressed higher levels of HRASG12V than TKTB6-RAS, caused severe loss of grip strength. G, Tumors derived from TKTB34-RAS transformed cells caused reduction in EDL muscle weight.
Data from Mutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer
Authors: Wang Ruizhong , Khatpe Aditi S. , Kumar Brijesh , Mang Henry Elmer , Batic Katie , Adebayo Adedeji K. , Nakshatri Harikrishna
Published: May 2024

Abstract
Cancer-induced skeletal muscle defects differ in severity between individuals with the same cancer type. Cancer subtype-specific genomic aberrations are suggested to mediate these differences, but experimental validation studies are very limited. We utilized three different breast cancer patient-derived xenograft (PDX) models to correlate cancer subtype with skeletal muscle defects. PDXs were derived from brain metastasis of triple-negative breast cancer (TNBC), estrogen receptor–positive/progesterone receptor–positive (ER+/PR+) primary breast cancer from a BRCA2-mutation carrier, and pleural effusion from an ER+/PR− breast cancer. While impaired skeletal muscle function as measured through rotarod performance and reduced levels of circulating and/or skeletal muscle miR-486 were common across all three PDXs, only TNBC-derived PDX activated phospho-p38 in skeletal muscle. To further extend these results, we generated transformed variants of human primary breast epithelial cells from healthy donors using HRASG12V or PIK3CAH1047R mutant oncogenes. Mutations in RAS oncogene or its modulators are found in approximately 37% of metastatic breast cancers, which is often associated with skeletal muscle defects. Although cells transformed with both oncogenes generated adenocarcinomas in NSG mice, only HRASG12V-derived tumors caused skeletal muscle defects affecting rotarod performance, skeletal muscle contraction force, and miR-486, Pax7, pAKT, and p53 levels in skeletal muscle. Circulating levels of the chemokine CXCL1 were elevated only in animals with tumors containing HRASG12V mutation. Because RAS pathway aberrations are found in 19% of cancers, evaluating skeletal muscle defects in the context of genomic aberrations in cancers, particularly RAS pathway mutations, may accelerate development of therapeutic modalities to overcome cancer-induced systemic effects.
Significance:
Mutant RAS- and PIK3CA-driven breast cancers distinctly affect the function of skeletal muscle. Therefore, research and therapeutic targeting of cancer-induced systemic effects need to take aberrant cancer genome into consideration.
Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody–Drug Conjugate Targeting Fibroblast Activation Protein
Authors: Gallant Joseph P. , Hintz Hallie M. , Gunaratne Gihan S. , Breneman Matthew T. , Recchia Emma E. , West Jayden L. , Ott Kendahl L. , Heninger Erika , Jackson Abigail E. , Luo Natalie Y. , Rosenkrans Zachary T. , Hernandez Reinier , Zhao Shuang G. , Lang Joshua M. , Meimetis Labros , Kosoff David , LeBeau Aaron M.
Published: May 2024

Cancer-associated fibroblasts (CAF) are a prominent cell type within the tumor microenvironment (TME) where they are known to promote cancer cell growth and survival, angiogenesis, drug resistance, and immunosuppression. The transmembrane prolyl protease fibroblast activation protein (FAP) is expressed on the surface of highly protumorigenic CAFs found in the stroma of nearly every cancer of epithelial origin. The widespread expression of FAP has made it an attractive therapeutic target based on the underlying hypothesis that eliminating protumorigenic CAFs will disrupt the cross-talk between components of TME resulting in cancer cell death and immune infiltration. This hypothesis, however, has never been directly proven. To eliminate FAP-expressing CAFs, we developed an antibody–drug conjugate using our anti-FAP antibody, huB12, coupled to a monomethyl auristatin E (huB12-MMAE) payload. After determining that huB12 was an effective targeting vector, we found that huB12-MMAE potently eliminated FAP-expressing cells as monocultures in vitro and significantly prolonged survival in vivo using a xenograft engineered to overexpress FAP. We investigated the effects of selectively eliminating CAFs using a layered, open microfluidic cell coculture platform, known as the Stacks. Analysis of mRNA and protein expression found that treatment with huB12-MMAE resulted in the increased secretion of the proinflammatory cytokines IL6 and IL8 by CAFs and an associated increase in expression of proinflammatory genes in cancer cells. We also detected increased secretion of CSF1, a cytokine involved in myeloid recruitment and differentiation. Our findings suggest that the mechanism of FAP-targeted therapies is through effects on the immune microenvironment and antitumor immune response.

Significance:

The direct elimination of FAP-expressing CAFs disrupts the cross-talk with cancer cells leading to a proinflammatory response and alterations in the immune microenvironment and antitumor immune response.
Likeness across Nature
Authors: Cooley Mackenzie
Published: May 2024

Over the course of a long career, Hieronymus Fabricius of Aquapendente sought to train students and readers to think across nature. This article suggests that we read his program as inculcating an “anatomical eye”: a visual language of the body’s logic and nature’s intention that encoded knowledge, which expert anatomists derived from touch and sight combined. Fabricius both taught and learned haptically, observing organs’ divisions through variations in texture and measuring the differences in reproductive anatomy across animals with his fingers. Through dissections of sheep, cattle, horses, sharks, guinea pigs, dogs, and humans, he gathered details about how nature had produced both startling likenesses and particularities across the animal kingdom. While artists sometimes struggled to capture his experience, Fabricius’s longstanding commitment to working with them revealed that, whatever the challenges, the potential for expanding the “anatomical eye,” and the reputation that came with it, was worth the risk.
Chimonobambusa multiramosa (Poaceae, Bambusoideae), a new bamboo species from northeast Yunnan, China
Authors: ZHANG YI–TING , CAO AN–JIANG , DING YU–LONG
Published: May 2024

Chimonobambusa multiramosa, a new species from Yunnan, China, is described and illustrated. This new species is morphologically similar to C. ningnanica, but differs in having much more branches per culm node, culm leaf sheaths longer than the internodes and sheath-scar bearing tardily deciduous haris. Based on the morphological features, this new species is assigned to Chimonobambusa sect. Oreocalamus.