Published in Promise & Progress - Promise & Progress 2018

Raman’s drug discovery began with research to understand the effect of secondhand smoke on breast cancer. It led him and his team to develop a first in-class drug called RK-33. Countless hours in the lab and hundreds of experiments and assays later, Raman and his team have developed and patented a small molecule inhibitor of the DDX3 gene, an exciting first-in-class pharmaceutical. Research that began in 2005 with funding from the Flight Attendant Medical Research Institute found that a gene called DDX3 was abundantly expressed in cells exposed to cigarette smoke.

Raman’s lab took a closer look at the gene, and when they blocked its function in animal models, tumors shrank, and the cancer didn’t spread. Tumors that spread from their original site, called metastatic, had the greatest expression of DDX3. “This finding fascinated me because metastatic cancers are the most difficult to treat,” says Raman. The DDX3 gene was already known to be instrumental in the replication of viruses, but no one had developed a way to block it. Working with a medicinal chemist, Raman came up with a series of potential drug compounds designed to inhibit DDX3 activity. After testing different combinations, the 33rd compound hit the target, and RK-33 was born. “That was a big day,” Raman says. “It’s when everything went from theory to reality. We had discovered a new way to attack one of the key enablers of cancerous activity.”

When Raman and his team first tested RK-33 in breast cancer cell lines, it had little effect on normal breast cells with low DDX3 expression. When they tested it in triple-negative breast cancer cells with high DDX3 expression, however, RK-33 easily killed the cancer cells. “If you imagine your hand as a cancerous tumor,” he says, referring to his mutation/fingertip analogy, “many of the drugs that we use to attack cancer act by cutting off a finger. There are still multiple other fingers left, and the rest of the hand can still function and evolve, leading to further spread and even adaptation of cancerous cells. RK-33 acts more like it is cutting off the wrist. When targeted successfully, it prevents a tumor’s access to other survival options. Any tumor-sustaining mutations are rendered useless to the cancer cell because it cannot replicate itself.”

Since RK-33 attacks overexpressed concentrations of DDX3 with greater intensity and efficacy, it should be toxic to tumors but not to the rest of the body Studies of the drug’s toxic effects on normal cells followed, and as Raman increased the dose of RK-33, it began to work against cancer cells with different levels of DDX3 expression but did not harm normal cells. “We did extensive toxicology experiments,” says Raman. “Even at four times the therapeutic dose, it was not toxic in animal models.” Since the project that originally led him to RK-33 involved smoking-associated cancer, Raman decided to also look at lung cancer, and he found it also had significant overexpression of DDX3. “I thought it was too good to be true,” says Raman. “We repeated and repeated the lung cancer studies, and we found out that in sample after sample, this gene was overexpressed. It couldn’t be a coincidence.”

Further studies showed the gene was overexpressed in many cancer types, including triple-negative breast cancer, one of the most treatment-resistant forms of breast cancer; lung cancer; prostate cancer; sarcoma; and colorectal cancer. With his DDX3 gene target appearing to play a role across cancer types and his DDX3-blocking drug RK-33 patented and in development, Raman went back to the laboratory to decipher exactly how his drug worked at the cellular level. “The gene is a critical part of the body’s DNA repair mechanism,” says Raman. “Cancer cells use it to reproduce and maintain the genetic stability essential to their survival.”

Raman found that blocking the gene with RK-33 not only killed cancer cells directly but also sensitized them to treatment with radiation therapy. Radiation therapy kills cancer cells by damaging cell DNA beyond its ability to make repairs. Cancer cells that survive treatment do so because they are able to repair their DNA. Raman says RK-33 helps disable this repair mechanism. “If you irradiate cells, their DNA strands break, but over a short period of time, they get repaired. When you add RK-33, the strands remain broken. The cells cannot make repairs.” This finding led Raman to patent his drug as a radiation therapy sensitizer, but the evidence from his research shows it does more. One of the most exciting characteristics of RK-33 is its ability to destroy metastatic cancers—the often-lethal cancers that spread from the original site of a tumor and seed new, treatment-resistant tumors in different parts of the body.

Metastatic breast cancers have very high levels of DDX3. “Metastasis to the bone, brain and lung is common in cancer, but there are few drugs that have any long-lasting impact against metastatic cancers,” says Raman. RK-33 could be the critical difference-maker in the fight against these entrenched, often terminal, cancers. “Currently, there is no curative treatment for brain cancer metastasis,” he says. “It’s hard to find a silver bullet for cancer, but because RK-33 is nontoxic and a phenomenal radiosensitizer, there are so many opportunities, including metastatic cancers.” The potential to offer better outcomes to patients with the most difficult diagnoses is what Raman is most excited about. He offers a list of possibilities. “Advanced prostate and colon cancer, sarcoma (bone cancer), brain tumors, inflammatory breast cancer—all these indications are looking promising in multiple cancer models,” he says. “We think RK-33 will work in any cancer that requires DDX3. And so far, all these difficult cancers require DDX3.

“My father is a colon cancer survivor,” says Raman, “but unfortunately, not every patient responds to our current treatments. This compound represents a chance to change outcomes and save lives, and that’s the best of what advanced biological research is about.” Raman is now in the last stages of refining RK-33. Because of its broad application, low toxicity and ability to sensitize cancer cells to radiation therapy, Raman wants a formulation that can be used in both adult and pediatric patients. His goal is to have a drug ready to go to patients in clinical trial within the year. “We have a lot of pediatric cancer patients at Hopkins, and we are constantly looking to develop solutions that improve their outcomes,” says Raman. Raman draws inspiration from a particular patient. “Tara is a young girl who was diagnosed with a metastatic bone cancer called sarcoma two weeks before her 4th birthday,” says Raman. “Currently, there is no standard of care for her disease because all treatments have worked so poorly. Nearly 80 percent of metastatic sarcoma patients relapse within two years of being diagnosed, and five-year survival is less than 20 percent. “Hopefully this drug will offer new hope and better outcomes for patients like Tara and their families,” Raman says. “That’s why we’re pushing to get RK-33 into human trials as fast as we can.”

Despite these promising discoveries, Raman is now facing what is known as the “valley of death.” Funding needs escalate rapidly as the drug is tested in humans and then across larger populations, and progress on the new drug will likely slow, or even stop, as he applies for more grants and appeals to more donors. His immediate goal is to obtain enough funding to complete the costly experiments required to file an Investigational New Drug application with the FDA.

The Flight Attendant Medical Research Institute, Safeway, the Dutch Cancer Foundation, Alex’s Lemonade Stand Foundation, TEDCO and other funding partners have brought RK-33 this far, but Raman says that he needs about $3 million to $4 million more. “Like it or not,” Raman says, “the reality of the life sciences industry today is that the pace of getting new drugs to patients is controlled by investigators’ ability to find financial partners.” Standing by anxiously are his Kimmel Cancer Center clinical collaborators: radiation oncologist Phuoc Tran, pediatric sarcoma expert David Loeb and breast cancer expert Vered Stearns, who will lead the clinical studies in patients. “I am so lucky to work in a place like Hopkins. I have a great team working with me. From day one, all of them wanted to help—with no conditions. They are in it for the patients,” says Raman. “That’s essential because if you are trying to make advances against cancer, you need scientists and clinicians working together. I can’t think of an institution that does it better than the Kimmel Cancer Center.”