Akash Gunjan

Mutations in the DNA packaging and regulatory protein histone H3 and its primary sequence variants drive specific types of predominantly pediatric cancers, including the 10 incurable high-grade brain stem gliomas known as Diffuse Intrinsic Pontine Gliomas (DIPG). Up to 90% of DIPG tumors carry the lysine 27 to methionine (K27M) mutation in histone H3 variants, usually the histone H3.3 variant.  H3 K27M mutant high-grade pediatric gliomas such as DIPG do not currently have any approved therapies and are 100% fatal. The present invention is a therapeutic approach which targets specific molecular pathways that are aberrant only in the mutant tumor cells but not the wild type cells, i.e., a therapy in which only the H3 mutant tumor cells would be eliminated specifically, while the normal cells carrying wild type H3 would be largely spared.

This targeted approach can be pursued is a few different ways that are the focus of this invention.  

Steroids are commonly prescribed medications in the US and around the world. Topical steroids are used extensively to treat a wide range of skin disorders such as psoriasis, eczema and dermatitis, while local steroid injections are a mainline therapy for benign fibrotic skin tumors know as keloids. Additionally, oral steroids are to treat systemic autoimmune conditions, while inhaled steroids serve as the mainline therapy for long-term control of asthma and nasal allergies. However, there is a wide variation in the response of patients to steroid therapy. For example, only about 34% of keloid patients benefit from steroid therapy, while 49% do not respond to it and the remaining 17% of patients actually see a worsening of their symptoms upon steroid therapy. This variability in patients' responses to steroids is likely due to individual differences in the patients’ genetic or epigenetic makeup, although the genes or epigenetic pathways involved have not yet been identified. The highly variable patient responses to steroid therapy highlight the dire need for a screening test to determine patients’ response to steroids prior to initiating therapy.

Since all our cells reflect our genetic/epigenetic makeup, they are also potentially capable of accurately reporting our response to steroids. Hence, as long as we can obtain a biopsy sample from patients, we can test them for sensitivity to steroids.  We have identified six genes whose expression patters correlate well with response to steroids and have developed a simple method for screening patients to determine the effects of steroids. This qRT-PCR based molecular test can provide results in a few hours. In the future it may be possible to use an antibody based lateral flow rapid test that can provide results in minutes.

Keloids are disfiguring, painful, and itchy, but benign fibrotic skin tumors or lesions characterized by excessive dermal fibroblast proliferation and collagen deposition. They occur in susceptible individuals due to abnormal wound healing. Keloids are understudied, difficult to treat, and predominantly affect dark-skinned individuals. Their incidence is estimated to be as high as 1 in 6 among African Americans, compared to around 1 in 1000 among white Americans, suggesting that genetic and/or epigenetic factors contribute strongly to keloid disease. However, the molecular mechanisms involved in driving keloid formation in susceptible individuals are unclear.

Currently there are no standardized treatments available for keloids and they have very high recurrence rates upon surgical resection alone. Intralesional steroids are commonly used, albeit with highly variable responses. Furthermore, although superficial radiation therapy is emerging as one of the most effective post-surgical adjuvant therapies to prevent keloid recurrence, it requires specialized equipment and its association with cancer therapy leads to reluctance among both providers and patients for its use in keloid therapy.

Despite advances in medical research, there is still a scarcity of methods and compositions that are effective in the treatment of keloids that do not require specializedequipment and/or trips to a medical facility, as does radiation therapy. Hence, we have applied a multiplatform approach to identify multiple cellular pathways that can be targeted for keloid therapy using combinations of existing FDA approved or preclinical drugs applied topically. These drugs should greatly expand options for keloid therapy, especially through topical application, leading to a more personalized treatment options.