Michael Goldstein, MD, PhD

Assistant Professor of Radiation Oncology and Molecular Radiation Sciences
Department of Radiation Oncology
Division of Molecular Radiation Sciences
Radiation Oncology at Sibley Memorial Hospital

The Johns Hopkins University School of Medicine
Sidney Kimmel Cancer Center
401 North Broadway, Suite 1440
Baltimore, MD 21287
Tel:  410-502-9748
Fax:  410-502-2821
E-mail:  mgolds33@jhmi.edu

Our lab is studying the role of epigenetic pathways in cellular DNA damage responses with the main goal to identify new molecular targets in tumors and improve cancer care.

Dr. Goldstein’s laboratory investigates the molecular mechanisms of cellular responses to radiation- and chemotherapy-induced DNA damage. We specifically focus on glioblastoma, medulloblastoma, ependymoma and HPV-positive cancers as tumor models. Our primary aim is to identify new DNA damage response pathways that can be pharmacologically targeted in order to improve tumor response to genotoxic treatment by radiation and chemotherapy. We are specifically interested in epigenetic changes that occur at the sites of DNA damage including alteration of chromatin structure and post-translational modifications of histone proteins. These events are critical for repair of DNA lesions making epigenetic modifiers attractive targets for sensitization of cancer cells to radiotherapy and chemotherapy.

Our mission is to impact cancer patient care by developing new strategies that can enhance the efficacy of radiotherapy and chemotherapy by modulating DNA damage responses in cancer.

Epigenetic markers of radiation response in medulloblastoma
Medulloblastoma is the most common malignant brain tumor of the childhood. Radiotherapy is a critical treatment modality for this tumor as failure to control disease through radiation results in cancer recurrences that are usually fatal. Thus, understanding the mechanisms of radiation resistance in this tumor allows to significantly improve treatment outcomes. We have discovered a new epigenetic marker of radiation response in medulloblastoma demonstrating that loss of H3K27me3 results in tumor resistance to radiotherapy (Gabriel et al., Cancer Research, 2022). Further, we found that BET inhibitors can successfully mitigate this resistance in H3K27me3-deficient medulloblastoma and restore radiation response. Currently, we are employing mouse models of medulloblastoma to design a clinically applicable regimen of radiation combined with BET inhibitors that can be used in treatment of medulloblastoma patients that are H3K27me3 deficient. Together, our work aims at personalizing medulloblastoma treatment based on molecular features of the tumor.

Epigenetic modifiers promoting radiation response in HPV-positive cancers
Radiation therapy is an important treatment modality of locally advanced cervical cancer. Thus, understanding the mechanisms of radiation response in cervical cancer is critical for development of new treatment strategies that can overcome radiation resistance and improve survival in patients. Radiation kills cancer cells by inducing toxic DNA doubles-strand breaks (DSBs). Increasing evidence suggests that epigenetic changes at the sites of radiation-induced DSBs play a critical role in DNA repair. Identifying epigenetic pathways that are involved in radiation response in cervical cancer cells can result in development of new therapeutics that can overcome radiation resistance and improve the outcomes of the disease.

Infection with high-risk HPV subtypes, including HPV 16 and 18, is a common driver of cervical carcinogenesis, associated with over 80% of cervical cancers. The oncogenic properties of the HPV genome have been attributed to the E6 and E7 gene products that affect multiple cellular processes including cell cycle, DNA repair and epigenetic pathways such as histone acetylation and methylation. Consequently, expression of high-risk E6 and E7 genes results in an altered epigenetic landscape in HPV+ cancers.

We are using CRISPR/Cas9-based screening techniques to identify epigenetic modifiers that are involved in radiation response in HPV+ and HPV- cervical cancer. Further, we are elucidating the molecular mechanisms through which these epigenetic modifiers regulate DDR. Our ultimate goal is to identify new targets for radiosensitization that are specific for HPV+ and HPV- tumors.

Molecular guidance for optimization of proton radiotherapy
Proton radiotherapy is an emerging treatment for medulloblastoma due to its ability to restrict radiation doses to the tumor, while sparing healthy tissues. Whereas proton radiation also kills tumor cells by generating DSBs, proton-induced DNA breaks differ from those induced by conventional γ-radiation (photon radiation). A characteristic of proton radiation is the possibility to achieve a high linear energy transfer (LET) in irradiated tissues, resulting in highly complex, clustered DNA lesions that persist for a longer period of time. Clustered DSBs require orchestration of multiple DNA processing and repair pathways, including NHEJ, HR, and base excision repair (BER) for repair and survival of proton- induced DNA damage.

We are studying the differences in molecular responses to DNA damage induced by photon versus proton radiation. These investigations will extend our knowledge of radiation biology and identify potential targets for sensitization of tumors to different types of radiotherapy.

Targeting chemotherapy resistance in glioblastoma
Glioblastoma is one of the most frequent and the most aggressive primary malignant brain affecting both, pediatric and adult patients. Despite some advances in treatment, prognosis of glioblastoma remains poor with less than 5% of patients surviving 5 years after diagnosis. An adjuvant temozolomide chemotherapy combined with radiotherapy represents the standard-of-care for glioblastoma. Thus, tumor response to radiation and temozolomide is critical for patient survival. Temozolomide is an alkylating agent that induces methylation of DNA bases. Whereas, radiation directly induces DSBs, temozolomide-induced DNA lesions have to be converted into DSBs in a mismatch repair and proliferation dependent manner.

Glioblastoma is characterized by a frequent deregulation of epigenetic pathways due to mutations of histone modifiers. We are investigating epigenetic pathways that when defective result in glioblastoma resistance to the standard-of-care chemoradiotherapy. Furthermore, we are developing strategies to restore chemoradiotherapy response in these tumors by using targeted therapeutics. This investigation will contribute to the personalized medicine approach in treatment of glioblastoma by tailoring treatment based on the individual mutation profile of epigenetic modifiers and has a potential to improve outcomes of this aggressive disease.

Role of short-chain histone acylations in DNA damage response
Responses to DNA damage are important determinants of cell viability and mutagenesis. Following DNA damage induction, an intricate network of DDR signaling pathways is activated to enforce cell cycle arrest, DNA repair, and potentially cell death. The ability of a cell to detect and repair damaged DNA has a direct effect on cell survival after exposure to genotoxic stress. Importantly, many agents that are clinically used to treat cancer function by damaging DNA.

Therefore, the ability of tumor cells to cope with DNA damage induced by radiation and chemotherapy affects the efficacy of these treatment modalities and disease outcomes. DNA double-strand breaks (DSBs) are the most toxic DNA lesions and are considered the major trigger of cell death induced by radiation and chemotherapy. Consequently, a specific inhibition of DSB repair in cancer cells can improve radiation response and the overall outcome in cancer patients.

Epigenetic alteration of chromatin including chromatin structure changes and post-translational modifications (PTMs) of histone proteins collectively form a complex epigenetic landscape regulating transcription, replication, and DDR. We have discovered that eviction of the H2A/H2B histone dimers is facilitated by nucleolin at the DSB sites, an event that is critical for repair of the DNA breaks by non-homologous end-joining. Additionally, multiple histone PTMs have been identified that promote recruitment of DDR factors to the break. For instance, a simultaneous methylation of H4K20 and ubiquitination of H2AK15 is required for 53BP1 recruitment and, consequently, DSB repair demonstrating how an intricate histone PTM network facilitates DDR.

Acetylation of histone lysine residues occurs frequently throughout the entire epigenome and plays an important role in transcription and DDR. A recent discovery of novel short-chain histone lysine acylations including propionylation, crotonylation succinylation and β-hydroxy-butyrylation has extended the arsenal of histone modifications. Increasing evidence suggests that these PTMs regulate cellular processes such as transcriptional activity. We are studying the role of these novel histone modifications in cellular response to radiation-induced DSBs. Our goal is to identify specific histone sites that are modified by these acylations at the DSB. Further, we are interested in dissecting the molecular mechanisms through which these modifications regulate DDR. We are employing multiple experimental techniques including laser-microirradiation, immuno-fluorescence, endonuclease-based DNA repair assays and chromatin immunoprecipitation in order to elucidate the role of these histone PTMs in DDR.

Michael Goldstein, MD, PhD

Principal Investigator

Akhil Kotwal, PhD

Postdoctoral Fellow

Neetu Verma, PhD

Postdoctoral Fellow