Expanding Therapeutic Options for Lung Cancer Patients (The EXTOL Project)


IN PARTNERSHIP WITH STAND UP TO CANCER (2019-PRESENT)

Jedd Wolchok, MD, PhD, Memorial Sloan Kettering Cancer Center; Pasi Jänne, MD, PhD, Dana-Farber Cancer Institute; and Justin Gainor, MD, Massachusetts General Hospital - Principal Investigators

The Mark Foundation for Cancer Research funds research in memory of personalized medicine pioneer Dr. Waun Ki Hong

The Mark Foundation has awarded a three-year $6 million grant to support a new phase of discovery for a team of investigators developing, optimizing and integrating targeted therapies and immunotherapies to improve outcomes for patients with the most common and hardest to treat lung cancers. The team originally launched its collaborative effort in 2015 as a Stand Up to Cancer (SU2C)/American Cancer Society (ACS) dream team.  Principal investigators Jedd Wolchok, MD, PhD of Memorial Sloan Kettering Cancer Center, Justin Gainor, MD of Massachusetts General Hospital and Pasi Jänne, MD, PhD of Dana-Farber Cancer Institute will lead the team in new research that builds upon the substantial success the team has already achieved.

A deeper understanding of KRAS mutations and the drugs that target these tumor drivers

A major aim of the project will be to achieve a deeper understanding of the biology of a new class of drugs that inhibit the activity of KRAS, a mutant protein responsible for tumor formation in roughly 30 percent of lung cancers. By uncovering the mechanisms by which these drugs act and their effects in tumors with other genetic alterations in addition to those in KRAS, these pre-clinical studies will help physicians determine how to best utilize these therapies independently and in combination with other agents for maximal patient benefit. The team will also explore other biological pathways regulated by mutant KRAS as well as cellular processes that allow tumors to resist KRAS-targeted drugs with the ultimate goal of designing optimal combination therapies to circumvent tumor resistance and recurrence.

Data analytics to gauge and improve patient response to immunotherapies

Another major aim of the project will be the collection and comprehensive analysis of samples from lung cancer patients treated with immunotherapies at the multiple institutions involved in this grant. With funding from The Mark Foundation, the team will expand its collection of patient genomic and immune-profile information to include samples from patients before and during treatment, as well as from recipients of immunotherapy combinations, with the goals of determining the molecular changes caused by treatment and identifying changes tumors develop that render treatments ineffective in some patients. The team will be joined by Mark Foundation grantee Ben Greenbaum, PhD from Memorial Sloan Kettering Cancer Center and Marta Lusksza, PhD from Mt. Sinai Hospital’s Icahn School of Medicine, who will create new analytical platforms to maximally integrate the data and probe how tumors evolve genetically in ways that can lead to better or worse patient responses to treatment.

Additional researchers

The larger team comprises other world-renowned cancer researchers including: Gregory Riely, MD, PhD, Charles Rudin, MD, PhD, Taha Merghoub, PhD, Matthew Hellmann, MD, and Neal Rosen, MD, PhD of Memorial Sloan Kettering Cancer Center; Kevan Shokat, PhD of University of California, San Francisco; Cyril Benes, PhD, Aaron Hata, MD, PhD, and Justin Gainor, MD of Massachusetts General Hospital; Kwok-Kin Wong, MD, PhD, of New York University Langone Medical Center; David Barbie, MD of Dana Farber Cancer Institute; John Heymach, MD, PhD and Ferdinandos Skoulidis, MD, PhD, of MD Anderson Cancer Center; Nir Hacohen, PhD, of Harvard Medical School; Gad Getz, PhD and Arvind Ravi, MD, PhD of the Broad Institute; Drew Pardoll, MD, PhD of Johns Hopkins School of Medicine; and Roy Herbst, MD, PhD and Kurt Schalper, MD, PhD of Yale School of Medicine

About Dr. Waun Ki Hong

Dr. Waun Ki Hong was a renowned medical oncologist and physician-scientist who passed away on January 2, 2019. Among his numerous contributions to cancer research and treatment (particularly in personalized medicine), Dr. Hong helped change the standard of care for head and neck cancer. He led clinical trials which showed that chemotherapy and radiotherapy was an effective alternative to laryngectomy for cancer of the larynx. That discovery dramatically improved the quality of life for patients with this disease and helped lay a foundation for organ preservation in numerous cancer types.

published research

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Zhang Z, Gao R, Hu Q, Peacock H, Peacock DM, Dai S, Shokat KM, Suga H. GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf. ACS Cent Sci. 2020.

Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, Do A, Zubiri L, Stevens S, Vaughn J, Goodwin K, Gavralidis A, Willers H, Miller A, Farago A, Piotrowska Z, Lin JJ, Dagogo-Jack I, Lennes IT, Sequist LV, Temel JS, Heist RS, Digumarthy S, Reynolds KL, Gainor JF. Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep. 2021.

Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, Michel AG, Syed MU, Fella KA, Sakhi M, Baiev I, Juric D, Gainor JF, Klempner SJ, Lennerz JK, Siravegna G, Bar-Peled L, Hata AN, Heist RS, Corcoran RB. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. 2021.

Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, Johnson ML, Heist RS, Patil T, Riely GJ, Jacobson JO, Yang X, Persky NS, Root DE, Lowder KE, Feng H, Zhang SS, Haigis KM, Hung YP, Sholl LM, Wolpin BM, Wiese J, Christiansen J, Lee J, Schrock AB, Lim LP, Garg K, Li M, Engstrom LD, Waters L, Lawson JD, Olson P, Lito P, Ou SI, Christensen JG, Jänne PA, Aguirre AJ. Acquired Resistance to KRASG12C Inhibition in Cancer. N Engl J Med. 2021.

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Lopez de Rodas M, Schalper KA. Tumour antigen-induced T cell exhaustion – the archenemy of immune-hot malignancies. Nat Rev Clin Oncol. 2021.

Ricciuti B, Arbour KC, Lin JJ, Vajdi A, Vokes N, Hong L, Zhang J, Tolstorukov MY, Li YY, Spurr LF, Cherniack AD, Recondo G, Lamberti G, Wang X, Venkatraman D, Alessi JV, Vaz VR, Rizvi H, Egger J, Plodkowski AJ, Khosrowjerdi S, Digumarthy S, Park H, Vaz N, Nishino M, Sholl LM, Barbie D, Altan M, Heymach JV, Skoulidis F, Gainor JF, Hellmann MD, Awad MM. Diminished efficacy of PD-(L)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is impacted by KRAS mutation status. J Thorac Oncol. 2021.

Kobayashi Y, Chhoeu D, Li J, Price KS, Kiedrowski LA, Hutchins JL, Hardin AI, Wei Z, Hong F, Bahcall M, Gokhale PC, Jänne PA. Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers. Nature. 2022.

Shui B, La Rocca G, Ventura A, Haigis KM. Interplay between K-RAS and miRNAs. Trends Cancer. 2022.

Ricciuti B, Son J, Okoro JJ, Mira A, Patrucco E, Eum Y, Wang X, Paranal R, Wang H, Lin M, Haikala HM, Li J, Xu Y, Alessi JV, Chhoeu C, Redig AJ, Köhler J, Dholakia KH, Chen Y, Richard E, Nokin MJ, Santamaria D, Gokhale PC, Awad MM, Jänne PA, Ambrogio C. Comparative analysis and isoform-specific therapeutic vulnerabilities of KRAS mutations in non-small cell lung cancer. Clin Cancer Res. 2022.

Vasta JD, Peacock DM, Zheng Q, Walker JA, Zhang Z, Zimprich CA, Thomas MR, Beck MT, Binkowski BF, Corona CR, Robers MB, Shokat KMKRAS is vulnerable to reversible switch-II pocket engagement in cellsNat Chem Biol. 2022.

Johnson C, Burkhart DL, Haigis KM. Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention. Cancer Discov. 2022.

Schad SE, Chow A, Mangarin L, Pan H, Zhang J, Ceglia N, Caushi JX, Malandro N, Zappasodi R, Gigoux M, Hirschhorn D, Budhu S, Amisaki M, Arniella M, Redmond D, Chaft J, Forde PM, Gainor JF, Hellmann MD, Balachandran V, Shah S, Smith KN, Pardoll D, Elemento O, Wolchok JD, Merghoub T. Tumor-induced double positive T cells display distinct lineage commitment mechanisms and functions. J Exp Med. 2022.

Lopez de Rodas M, Nagineni V, Ravi A, Datar IJ, Mino-Kenudson M, Corredor G, Barrera C, Behlman L, Rimm DL, Herbst RS, Madabhushi A, Riess JW, Velcheti V, Hellmann MD, Gainor J, Schalper KA. Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer. J Immunother Cancer. 2022.

Ricciuti B, Wang X, Alessi JV, Rizvi H, Mahadevan NR, Li YY, Polio A, Lindsay J, Umeton R, Sinha R, Vokes NI, Recondo G, Lamberti G, Lawrence M, Vaz VR, Leonardi GC, Plodkowski AJ, Gupta H, Cherniack AD, Tolstorukov MY, Sharma B, Felt KD, Gainor JF, Ravi A, Getz G, Schalper KA, Henick B, Forde P, Anagnostou V, Jänne PA, Van Allen EM, Nishino M, Sholl LM, Christiani DC, Lin X, Rodig SJ, Hellmann MD, Awad MM. Association of High Tumor Mutation Burden in Non-Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels. JAMA Oncol. 2022.

Henick BS, Villarroel-Espindola F, Datar I, Sanmamed MF, Yu J, Desai S, Li A, Aguirre-Ducler A, Syrigos K, Rimm DL, Chen L, Herbst RS, Schalper KA. Quantitative tissue analysis and role of myeloid cells in non-small cell lung cancer. J Immunother Cancer. 2022.

Zhang Z, Guiley KZ, Shokat KM. Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S). Nat Chem Biol. 2022.

Ricciuti B, Alessi JV, Elkrief A, Wang X, Cortellini A, Li YY, Vaz VR, Gupta H, Pecci F, Barrichello A, Lamberti G, Nguyen T, Lindsay J, Sharma B, Felt K, Rodig SJ, Nishino M, Sholl LM, Barbie DA, Negrao MV, Zhang J, Cherniack AD, Heymach JV, Meyerson M, Ambrogio C, Jänne PA, Arbour KC, Pinato DJ, Skoulidis F, Schoenfeld AJ, Awad MM, Luo J. Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D mutated non-small cell lung cancer. Ann Oncol. 2022.

Griesinger F, Curigliano G, Thomas M, Subbiah V, Baik CS, Tan DSW, Lee DH, Misch D, Garralda E, Kim DW, van der Wekken AJ, Gainor JF, Paz-Ares L, Liu SV, Kalemkerian GP, Houvras Y, Bowles DW, Mansfield AS, Lin JJ, Smoljanovic V, Rahman A, Kong S, Zalutskaya A, Louie-Gao M, Boral AL, Mazieres J. Safety and efficacy of pralsetinib in RET fusion-positive non-small cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol. 2022.

Zhang Z, Rohweder PJ, Ongpipattanakul C, Basu K, Bohn MF, Dugan EJ, Steri V, Hann B, Shokat KM, Craik CS. A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. Cancer Cell. 2022.

Zhang Z, Fan Q, Luo X, Lou K, Weiss WA, Shokat KM. Brain-restricted mTOR inhibition with binary pharmacology. Nature. 2022.

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