Project 1. Harnessing therapy-induced chemokines to convert immune-desert "cold" tumors into "hot" t-cell inflamed tumors and promote anti-tumor immunity.
Description: Metastatic melanomas are aggressive tumors that respond poorly to chemotherapy and radiation and promptly acquire resistance to targeted therapy. While immune checkpoint inhibitors (ICIs) can induce sustained melanoma remission, nearly half of patients are intrinsically resistant to ICIs, in part because their tumors are too large to be cleared by the immune system or are immunologically “cold” and lack the immune recognition necessary to generate anti-tumor T effector cells. Our preliminary data show that certain therapies can enhance the production of T cell-attracting chemokines in the tumor by activating a melanoma-cell intrinsic pro-inflammatory transcriptional response.
We are investigating tumor-intrinsic pathways driving immunogenic tumor phenotype through chemokine production. Our aim is to identify specific pattern recognition receptors and inflammatory transcription factors activated in the conditions of drug-induced cellular stress. Moreover, we investigate how to harness the maximum benefit from drug-induced inflammatory response while limiting its negative consequences, such as persistent senescence. To this end, we explore senolytic approaches and rational combinations of pro-immunogenic drugs with new and emerging immuno-oncology agents.
Select publications:
Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy. A. Vilgelm, A. Richmond. Front. Immunol., 2019
Description: Metastatic melanomas are aggressive tumors that respond poorly to chemotherapy and radiation and promptly acquire resistance to targeted therapy. While immune checkpoint inhibitors (ICIs) can induce sustained melanoma remission, nearly half of patients are intrinsically resistant to ICIs, in part because their tumors are too large to be cleared by the immune system or are immunologically “cold” and lack the immune recognition necessary to generate anti-tumor T effector cells. Our preliminary data show that certain therapies can enhance the production of T cell-attracting chemokines in the tumor by activating a melanoma-cell intrinsic pro-inflammatory transcriptional response.
We are investigating tumor-intrinsic pathways driving immunogenic tumor phenotype through chemokine production. Our aim is to identify specific pattern recognition receptors and inflammatory transcription factors activated in the conditions of drug-induced cellular stress. Moreover, we investigate how to harness the maximum benefit from drug-induced inflammatory response while limiting its negative consequences, such as persistent senescence. To this end, we explore senolytic approaches and rational combinations of pro-immunogenic drugs with new and emerging immuno-oncology agents.
Select publications:
Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy. A. Vilgelm, A. Richmond. Front. Immunol., 2019
Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment. A. Vilgelm, C. Johnson, Nripesh Prasad, Jinming Yang, Sheau-Chiann Chen, G. Ayers, Jeff S. Pawlikowski, D. Raman, J. Sosman, M. Kelley, J. Ecsedy, Y. Shyr, S. Levy, A. Richmond. Journal of the National Cancer Institute, 2016
BCL-xL inhibition potentiates cancer therapies by rewiring the p53 protein network to enable senescence to apoptosis cell fate switch. Vijaya Bharti1, Reese Watkins1, Amrendra Kumar1, Chengli Shen2, Rebecca L. Shattuck-Brandt3,4, Allan Tsung2, Alex Davies5, Catherine Chung1, Vivian L. Weiss6, Ann Richmond3,4, Anna E. Vilgelm1,7. Coming out soon...
BCL-xL inhibition potentiates cancer therapies by rewiring the p53 protein network to enable senescence to apoptosis cell fate switch. Vijaya Bharti1, Reese Watkins1, Amrendra Kumar1, Chengli Shen2, Rebecca L. Shattuck-Brandt3,4, Allan Tsung2, Alex Davies5, Catherine Chung1, Vivian L. Weiss6, Ann Richmond3,4, Anna E. Vilgelm1,7. Coming out soon...
Project 2. Immunologic vulnerabilities associated with CDK4/6 inhibitor therapy
Description: Cyclin-dependent kinases 4 and 6 (CDK4/6) are proteins that become overactive in breast cancer cells causing cancer cells to divide uncontrollably, which results in tumor growth over time. CDK4/6 inhibitors, such as palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), are approved by the FDA and are routinely used in combination with hormonal therapy to stop the progression of metastatic breast cancer. CDK4/6 inhibitors put brakes on CDK4 & 6 proteins and this delays cancer cells from dividing. However, over time tumors find ways to escape the effect of these drugs and stop responding. When this happens, tumors resume uncontrolled growth and dissemination to organs throughout the body. We have rationalized that combining CDK4/6 inhibitors with agents that can kill cancer cells weakened by the CDK4/6 inhibitor treatment will cause tumor-shrinking and prevent relapses.
Our work towards finding a translatable solution to CDK4/6 inhibitor resistance uncovered unique vulnerabilities of CDK4/6 inhibitor-treated tumors to certain immuno-oncology agents. We are employing functional precision oncology and multi-omics platforms to understand the mechanisms of immune vulnerability associated with CDK4/6 inhibitor treatment and develop novel therapeutic combinations based on these findings.
Select publications:
Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors. R. Uzhachenko, V. Bharti, Z. Ouyang, Ashlyn Blevins, S. Mont, Nabil Saleh, Hunter Lawrence, Chengli Shen, Sheau-Chiann Chen, G. Ayers, D. DeNardo, C. Arteaga, A. Richmond, A. Vilgelm. Cell reports, 2021
MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. A. Vilgelm, Nabil Saleh, R. Shattuck-Brandt, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chiann Chen, C. Johnson, Jinming Yang, Ashlyn Blevins, Chi Yan, Douglas B. Johnson, Rami N. Al-Rohil, Ensar Halilovic, Rondi M. Kauffmann, M. Kelley, G. Ayers, A. Richmond. Science Translational Medicine, 2019
Description: Cyclin-dependent kinases 4 and 6 (CDK4/6) are proteins that become overactive in breast cancer cells causing cancer cells to divide uncontrollably, which results in tumor growth over time. CDK4/6 inhibitors, such as palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), are approved by the FDA and are routinely used in combination with hormonal therapy to stop the progression of metastatic breast cancer. CDK4/6 inhibitors put brakes on CDK4 & 6 proteins and this delays cancer cells from dividing. However, over time tumors find ways to escape the effect of these drugs and stop responding. When this happens, tumors resume uncontrolled growth and dissemination to organs throughout the body. We have rationalized that combining CDK4/6 inhibitors with agents that can kill cancer cells weakened by the CDK4/6 inhibitor treatment will cause tumor-shrinking and prevent relapses.
Our work towards finding a translatable solution to CDK4/6 inhibitor resistance uncovered unique vulnerabilities of CDK4/6 inhibitor-treated tumors to certain immuno-oncology agents. We are employing functional precision oncology and multi-omics platforms to understand the mechanisms of immune vulnerability associated with CDK4/6 inhibitor treatment and develop novel therapeutic combinations based on these findings.
Select publications:
Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors. R. Uzhachenko, V. Bharti, Z. Ouyang, Ashlyn Blevins, S. Mont, Nabil Saleh, Hunter Lawrence, Chengli Shen, Sheau-Chiann Chen, G. Ayers, D. DeNardo, C. Arteaga, A. Richmond, A. Vilgelm. Cell reports, 2021
MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. A. Vilgelm, Nabil Saleh, R. Shattuck-Brandt, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chiann Chen, C. Johnson, Jinming Yang, Ashlyn Blevins, Chi Yan, Douglas B. Johnson, Rami N. Al-Rohil, Ensar Halilovic, Rondi M. Kauffmann, M. Kelley, G. Ayers, A. Richmond. Science Translational Medicine, 2019
Project 3. Understanding and overcoming CTCL therapy resistance.
Description: Cutaneous T cell lymphoma (CTCL) is a type of lymphoma in which malignant T cells are predominantly localized
to the skin and may also involve the lymph nodes, blood, or viscera. Patients with advanced disease require
systemic therapy. Several FDA-approved and off-label therapies are used for CTCL, but response rates are
typically low (25-40%) and often short-lived (1, 2) in advanced disease. Sequential use of available therapies
until options are exhausted is typical, and the survival is very poor at 1.4-3.8 years (3). Thus, there is an urgent
unmet need to understand and overcome CTCL therapeutic resistance.
The role of the tumor microenvironment (TME) in cancer progression and therapeutic response is increasingly
appreciated (4). Notably, CTCL is defined by its unique TME. Unlike other lymphomas that arise in lymph nodes
and lymphatic tissues, CTCL cells reside and proliferate within the skin. Clinical and histological evidence
suggests that non-malignant cells within the skin microenvironment interact with malignant T cells and these
interactions contribute to CTCL pathogenesis, progression, and immune evasion (5-9). This is strongly supported
by multimodal single-cell analysis showing that clonally matched skin resident and circulating CTCL cells have
distinct proliferation rates and gene expression signatures (10). Furthermore, CTCL-TME interactions modulate
the efficacy of CTCL therapies, including standard of care HDAC inhibitor romidepsin (11). Thus, targeting these
interactions is likely to improve therapeutic outcomes. However, our ability to define and validate the TME targets
is limited because no experimental models of CTCL with autologous TME exist.
We use the autologous tumor-normal 3D co-culture approach developed by our group to develop fully autologous CTCL patient-derived models recapitulating unique CTCL microenvironment ex vivo. We use these models to uncover and target key protective factors produced by the microenvironment cells that promote malignant CTCL cell growth and drug resistance.
Select publications:
Fine-Needle Aspiration-Based Patient-Derived Cancer Organoids. A. Vilgelm, Kensey Bergdorf, Melissa M. Wolf, V. Bharti, R. Shattuck-Brandt, Ashlyn Blevins, Caroline Y. Jones, Courtney J. Phifer, Mason A. Lee, C. Lowe, Rachel A Hongo, K. Boyd, J. Netterville, S. Rohde, K. Idrees, Joshua A. Bauer, D. Westover, Bradley I. Reinfeld, N. Baregamian, A. Richmond, W. Rathmell, Ethan Lee, O. McDonald, V. Weiss. iScience, 2020
Description: Cutaneous T cell lymphoma (CTCL) is a type of lymphoma in which malignant T cells are predominantly localized
to the skin and may also involve the lymph nodes, blood, or viscera. Patients with advanced disease require
systemic therapy. Several FDA-approved and off-label therapies are used for CTCL, but response rates are
typically low (25-40%) and often short-lived (1, 2) in advanced disease. Sequential use of available therapies
until options are exhausted is typical, and the survival is very poor at 1.4-3.8 years (3). Thus, there is an urgent
unmet need to understand and overcome CTCL therapeutic resistance.
The role of the tumor microenvironment (TME) in cancer progression and therapeutic response is increasingly
appreciated (4). Notably, CTCL is defined by its unique TME. Unlike other lymphomas that arise in lymph nodes
and lymphatic tissues, CTCL cells reside and proliferate within the skin. Clinical and histological evidence
suggests that non-malignant cells within the skin microenvironment interact with malignant T cells and these
interactions contribute to CTCL pathogenesis, progression, and immune evasion (5-9). This is strongly supported
by multimodal single-cell analysis showing that clonally matched skin resident and circulating CTCL cells have
distinct proliferation rates and gene expression signatures (10). Furthermore, CTCL-TME interactions modulate
the efficacy of CTCL therapies, including standard of care HDAC inhibitor romidepsin (11). Thus, targeting these
interactions is likely to improve therapeutic outcomes. However, our ability to define and validate the TME targets
is limited because no experimental models of CTCL with autologous TME exist.
We use the autologous tumor-normal 3D co-culture approach developed by our group to develop fully autologous CTCL patient-derived models recapitulating unique CTCL microenvironment ex vivo. We use these models to uncover and target key protective factors produced by the microenvironment cells that promote malignant CTCL cell growth and drug resistance.
Select publications:
Fine-Needle Aspiration-Based Patient-Derived Cancer Organoids. A. Vilgelm, Kensey Bergdorf, Melissa M. Wolf, V. Bharti, R. Shattuck-Brandt, Ashlyn Blevins, Caroline Y. Jones, Courtney J. Phifer, Mason A. Lee, C. Lowe, Rachel A Hongo, K. Boyd, J. Netterville, S. Rohde, K. Idrees, Joshua A. Bauer, D. Westover, Bradley I. Reinfeld, N. Baregamian, A. Richmond, W. Rathmell, Ethan Lee, O. McDonald, V. Weiss. iScience, 2020
