2013-2015 Movember-PCF Challenge Award ($1 Million)
Project Title: Co-targeting the Cell Cycle and Androgen Signaling Axis via CDK4/6 Inhibition and Androgen Deprivation: A Novel Paradigm for treating Metastatic Hormone-sensitive Prostate cancer
Principal Investigator: Maha Hussain, MD (University of Michigan)
Co-investigators: Felix Feng, MD (University of Michigan), Karen Knudsen, PhD (Thomas Jefferson University).
Description: Once prostate cancer metastasizes, or spreads, beyond the prostate gland, the vast majority of patients will ultimately succumb to this disease. Prostate cancer (PCa) spread is fueled by male hormones, or androgens, and the androgen receptor (AR) protein. For over 70 years, androgen deprivation therapy (ADT) has served as first-line treatment of men with metastatic PCa. Most men diagnosed with metastatic PCa have tumors that respond to ADT and their disease is said to be “hormone sensitive.” However, most men with hormone-sensitive PCa will eventually develop resistance to ADT. At that point, their disease is said to be treatment-resistant and mostly insensitive to hormone therapy. Prognosis at this stage is grim. Drs. Hussain, Feng and Knudsen will undertake an ambitious first-in-field investigation to determine if men with hormone-sensitive, metastatic PCa who are given a novel combination of drugs can delay the onset of resistance to ADT, and thus delay progression to end-stage disease.
The researchers will conduct a randomized, multi-center Phase II clinical trial in which men with metastatic hormone-sensitive PCa, whose tumors express a genetic alteration of the RB gene that can be targeted, will be randomly assigned to receive either ADT alone or ADT in combination with an experimental oral drug known as PD-0332991. The experimental compound inhibits CDK4/6, two kinase proteins that play a key role in cell growth cycles. Inhibiting CDK4/6 kinases may block cancer cell growth and can re-boot the activity of the retinoblastoma (RB) tumor suppressor gene. The tumor suppressor activity of the RB gene is often weakened in tumors, and to date, CDK4/6 inhibitors have shown significant anti-tumor effects against breast cancer. Preliminary data from these Challenge Award researchers shows that loss of RB tumor suppressor activity is found in 60% of men with far-advanced treatment-resistant PCa; however 80 to 90% of men with hormone-sensitive PCa (HSPC) continue to have some RB tumor suppressor activity. This Challenge Award team has also found that alterations in RB tumor suppressor activity have a direct impact on the function of the androgen receptor and can lead to AR malfunction which leads to end-stage, treatment-resistant disease.
In the clinical trial, patients will undergo biopsies of a metastatic site to determine their level of RB activity. This will greatly aid in future determinations of which patients with metastatic HSPC would likely benefit from this combination therapy. The team, using the metastatic biopsy samples from the Phase II clinical trial, will use genomic sequencing to determine other biomarkers that may make men good candidates for combination therapy of ADT and CDK4/6 inhibitors.
What this means for patients: Currently there is no cure for patients with metastatic treatment-resistant prostate cancer. This trio of researchers will combine a novel drug being developed by Pfizer—the candidate drug boosts the activity of a vital tumor suppressor gene and interrupts cancer cell growth cycles—with traditional androgen deprivation therapy in an attempt to prevent or delay cancer progression to end-stage disease. The novel investigational drug was recently shown to be safe and effective against a common form of advanced breast cancer. In the clinical trial, men whose tumors have functioning (RB) tumor suppressor gene activity—such men are the most likely responders and thus the best candidates for this new drug—will be given either the combination of drugs or ADT alone. This work is a study in precision medicine and may not only lead to the rapid development of a novel drug against PCa, it may well enable doctors to determine at the outset of therapy which men will be the strongest responders to this combination therapy.
2013-2016 Movember-PCF Challenge Award ($1.5 Million)
Project Title: Targeting BET Bromodomain Proteins: A Novel Therapeutic Strategy for Treatment Resistant Prostate Cancer
Principal Investigator: Arul Chinnaiyan, MD, PhD (University of Michigan)
Co-investigators: Shaomeng Wang, PhD (University of Michigan), Felix Feng, MD (University of Michigan), Irfan Asangani, PhD (University of Michigan).
Description: Prostate cancer is fueled by male hormones or androgens, such as testosterone. Those androgens bind to a protein known as the androgen receptor (AR). When it is activated by binding to androgens, the AR protein becomes a sort of androgen superhighway into the cell’s nucleus where it can act as a regulator of genes, turning them on or off. The vast majority of end-stage, treatment-resistant prostate cancer is driven by such AR “signaling.” Currently many anti-prostate cancer therapies target this AR signaling pathway, attempting to disrupt its pro-cancer activity by blocking either androgen production or blocking the activity of the AR protein itself. However, while responses to such therapies are often robust and extend men’s survival times, ultimately most men will develop resistance to these existing therapies. Drs. Chinnaiyan, Wang and Feng will use this Challenge Award to develop a completely new method of targeting the AR signaling pathway. They will develop an entirely new drug that prevents the genes the AR protein regulates from being turned “on” and making their protein products which act to drive cancer progression. This novel approach to “downstream” targeting of the AR signaling pathway may be used alone or in conjunction with conventional “upstream” anti-androgen drugs such as Zytiga or Xtandi. The researchers believe that such a “downstream” approach may prove more durable and that it will be less likely for men to develop resistance to their novel drug because most mechanisms of resistance are upstream of the drug target.
This team of researchers discovered that the AR physically interacts with a protein (BRD4) in the family of proteins known as BET bromodomain proteins. They also found that after treatment with BET-bromodomain inhibitor, called JQ1, the interaction between AR and BRD4 was blocked and pro-cancer genes downstream of AR were not called into action. They also found JQ1 to be more effective, in animal models of PCa, against tumor growth than Xtandi. While JQ1 is a useful laboratory compound, it does not have optimum drug properties for clinical use. Therefore, Chinnaiyan and his team plan to develop a novel, highly potent bromodomain inhibitor that is best suited to fight advanced prostate cancer with improved potency and drug properties compared to other clinically available bromodomain inhibitors. The team will do all the needed work to bring this highly promising therapeutic advance to a clinical trial in the shortest amount of time possible. They will also design a rational clinical trial that tests their novel drug in patients with advanced PCa that is resistant to conventional therapies.
What this means for patients: While the past few years have seen significant improvements in therapies for treatment-resistant prostate cancer, the overall survival times for men once their disease reaches this advanced stage remains tragically short. Dr. Chinnaiyan and his team will employ an entirely new way to hit back at treatment-resistant prostate cancer by developing, optimizing and functionally evaluating a new class of drug against treatment-resistant PCa. Because this drug works against PCa in a unique way, it may likely be used in conjunction with existing therapies to multiple anti-tumor effects.
2013-2015 Movember-PCF Challenge Award ($1 Million)
Project Title: Biomarkers of Therapeutic Response and Resistance to Androgen Receptor Signaling Inhibitors
Principal Investigator: Josh Lang, MD (University of Wisconsin)
Co-investigators: David Beebe, PhD (University of Wisconsin), Justine Bruce, MD, (University of Wisconsin), Mark Stein, MD (Robert Wood Johnson Medical School).
Description: As their name implies, circulating tumor cells (CTCs) are cancer cells that have sloughed off tumors and entered the blood stream. Recent technological advances have made it possible to capture these rare CTCs from a simple blood draw from a patient with the hope they can be used as a “liquid biopsy” of the patient’s cancer. Dr. Lang and colleagues have developed a system of CTC capture and subsequent analysis that is so sensitive it is able to isolate one CTC out of 20 million blood cells. Their device/technology platform is called VERSA, for Vertical Exclusion-based Rare Sample Analysis. The VERSA platform vastly improves upon other CTC capture methods previously developed, acting as a version 4.0 of CTC capture. VERSA not only allows for enumeration of how many CTCs are circulating in a patient’s blood stream, which can be a marker for metastatic disease progression or spread throughout the body, it can also perform multiple functions that enable doctors to better understand an individual patient’s cancer type and tailor medications and dosages that are most likely to help that patient.
For example, from a single blood draw, VERSA can analyze one CTC to determine the exact mutations in that cancer cell and compare those mutations to another CTC from the same patient. If drugs are available that target the mutations found, doctors can identify the drug or drug combination most likely to benefit each patient. In addition, because CTCs are far more easy—not to mention less painful—to extract from a patient with metastatic cancer, than performing bone biopsies, serial analysis of a patient’s CTCs can readily be performed to determine if additional mutations are acquired during disease progression, and if so, drug therapy can be altered accordingly. In addition, VERSA can determine in real-time how well a patient is responding to a given drug or therapy and treatment can be altered rapidly to minimize patient discomfort and maximize patient response to treatment. In this Challenge Award, Dr. Lang and his team will carry out the necessary work to automate and validate VERSA so that it can be used across the country in both large hospitals and small. They will conduct a multi-site clinical trial that uses VERSA to examine individual patient’s initial and ongoing reactions to treatment with two drugs (Xtandi and the investigational compound ARN-509) that target a key driver of prostate cancer progression—the androgen receptor. Drugs that target the androgen receptor have clearly been shown to benefit many men with advanced, metastatic prostate cancer; however, ultimately, even men who respond well to these drugs eventually develop resistance to them. This research, by Drs. Lang, Beebe, Bruce and Stein, will help determine how and why men develop resistance to AR-targeting drugs and what might be done to prevent or stall the development of drug resistance.
What this means for patients: Understanding cancer at the individual level is the goal of personalized and precision medicine. Dr. Lang and his team have developed an advanced technology that will allow doctors to peer into the individual cancer cell at the molecular level to determine what is driving a cancer at each stage of progression. This is a very important step in the ability to fully personalize cancer treatments to each patient’s cancer, even to each tumor in patients with metastatic disease. Dr. Lang and his team are developing and validating a new blood testing technology that can monitor disease progression, patient response to treatment, and the unique genetic fingerprint of individual cancer cells so treatment by location or type of mutation might be delivered. Their technology platform, VERSA, will also be used to understand why some patients are initially resistant to certain anti-cancer medications or become so as treatment progresses. This understanding can then be used to develop ways to prevent drug resistance and extend patient survival.
2013-2015 Movember-PCF Challenge Award ($1 Million)
Project Title: Understanding the Role of Tumor Heterogeneity of Treatment Resistant Prostate Cancer Using Avataroid Technology
Principal Investigator: Yu Chen, MD, PhD (Memorial Sloan-Kettering Cancer Center)
Co-investigators: Howard Scher, MD (MSKCC), James Hicks, PhD (Cold Spring Harbor Laboratory), Binzhi Qian, PhD (MSKCC), Brett Carver, MD (MSKCC), Daniel Danila, MD (MSKCC), Anuradha Gopalan, MD (MSKCC), Stephen Solomon, MD (MSKCC).
Scientists have known that prostate cancer cells are vastly different, or heterogeneous, from one man to another, and even vastly different from one tumor site to another, in the same man. Yet to study prostate cancer, they’ve relied on a very limited number of prostate cancer (PCa) cell lines or animal models that broadly mimic the disease. Thus, to date, pre-clinical work in testing drugs against PCa, or why PCa cells become resistant to a certain drug therapy, had to be done as a sort of group experiment. But researchers were limited by available technology.
The very idea of being able to recreate in the laboratory an exact replica of a man’s prostate tumor that is genetically indistinguishable from his primary tumor or metastatic tumor in his body, once seemed like science-fiction. A holy grail of PCa research is to be able to recreate what can be thought of as avatars for each tumor in each man so that scientists can study the molecular and other interactions that occur inside a tumor, between cancer cells and in the tumor microenvironment. Such an avatar of a man’s unique tumor or tumors would not only allow researchers to study how a particular cancer develops and changes over time, potentially enabling therapies to be developed that would arrest cancer progression, it has the marvelous potential to lessen patient discomfort. Avatar technology would allow testing a drug in the lab to determine how an individual patient is likely to respond without having to subject the patient to drug side effects and toxicities in order to find out.
Dr. Chen and colleagues are taking the fiction out of this science. Using human PCa cells and a specific “miracle-grow” admixture of human growth factors and signaling compounds, they have generated such personalized tumor avatars. Known as “organoids,” or “tumoroids,” Chen et al, have established a highly efficient means of stably growing these cancer avatars in the laboratory. They’ve also shown that these organoids can easily be shipped to other labs—ease of transport would allow patients across the country, or even the world, to benefit from this technology.
Under this Challenge Award, Chen and his team will further develop this technology and investigate how their organoids can aid in making clinical decisions, such as which drug to give a patient and when. Their study will recruit ~10 men per year with treatment-resistant PCa who are about to start therapy with Xtandi or Zytiga or the experimental anti-androgen ARN-509. They will use circulating tumor cells taken from a patient’s blood or cells taken from patient biopsy samples to create organoids for each man, both before he begins treatment and after treatment. They will evaluate how well each man’s pair of organiods corresponds to that man’s clinical response to the drug. They will be able to interrogate the organoid at the molecular level to help elucidate why a man responded to a treatment or did not. This work is essential to bringing organoid technology into clinical use and will help establish the validity/reliability of organoid/tumoroid technology for PCa patients.
What this means for patients: Being able to know what drug will benefit a patient before it is administered or what can be done to prevent resistance to a drug from developing will mean far less suffering for patients and increased longevity. Dr. Chen and his team will prove that avatars—exact replicas of a patient’s tumor—can be routinely used to help doctors make clinical decisions such as what drug is most likely to help a particular patient. Apart from being able to “test first” on a tumor avatar rather than in a patient himself, this work will also greatly aid in novel drug discovery that can be then be targeted to men based upon the unique genetic makeup of their tumor or tumors.
2013-2016 Movember-PCF Challenge Award ($1.5 Million)
Project Title: Defining Therapeutic Approaches to Target AR Pathway-independent Prostate cancer (APIPC)
Principal Investigator: Peter Nelson, MD (Fred Hutchinson Cancer Research Center)
Co-investigators: Ken Pienta, MD (Johns Hopkins), Emmanuel Antonarakis, MD (Johns Hopkins), Michael Ittman, MD, PhD (Baylor College of Medicine), Colin Pritchard, MD, PhD (University of Washington).
Description: Androgens are male hormones such as testosterone. These hormones, and their receptor—the androgen receptor (AR)—are key drivers of prostate cancer (PCa) growth. Doctors have long used medical or surgical means to remove or block androgen sources in men with metastatic PCa. Such androgen deprivation therapy (ADT) is usually, highly effective initially at controlling these advanced cancers. ADT removes the androgens and suppresses signals from the AR to which tumor cells are “addicted.” However, in most cases, PCa treated with ADT eventually progress to ADT-resistant PCa, an aggressive and often lethal stage of PCa. Recently second-generation anti-androgens have come to market that extend survival times for men with ADT-resistant tumors, but ultimately most men develop resistance to these drugs as well—an almost uniformly fatal development.
In the majority of men with ADT-resistant prostate cancer, tumors remain dependent upon AR signaling. However, a subset of men with ADT-resistant PCa have tumors that can grow and thrive even when AR signaling is completely absent. When this occurs the PCa is unresponsive to therapies that target androgens and the AR. Currently there is no effective treatment for androgen pathway-independent PCa.
Dr. Nelson and his team will use this Challenge Award to discover new ways to treat androgen pathway-independent PCa. They hypothesize that in the future the use of multiple drugs—either those now on the market or yet to come—to completely extinguish androgens and AR signaling will cure some men with ADT-resistant PCa, but leave others with an evolved form of PCa that the team has dubbed Androgen Receptor Pathway Independent Prostate Cancer, or APIPC.
Drs. Nelson, Pienta, Antonarakis, Pritchard and Ittman will determine the molecular mechanisms that allow this evolution of cancer to occur and ways to prevent or delay the onset of APIPC. Preliminary work by this team strongly suggests that two protein groups, known as fibroblast growth factors (FGFs) and their receptors (FGFRs) are key drivers in the development of APIPC. In preclinical work they will validate the FGF/FGFR signaling pathway as an actionable driver of APIPC, and then design a clinical trial to test if inhibition of this pathway leads to improved outcomes for men suffering from advanced PCa. They will also develop novel PCa lab models that recapitulate the evolution of AR-dependent prostate cancers to APIPC to better understand this highly lethal subtype of disease and identify actionable drug targets to limit its development and progression.
What this means for patients: Dr. Nelson and his team will undertake extensive studies to determine how PCa that is dependent upon androgen signaling evolves to a state of AR-independence—the latter being extremely difficult to treat as currently no effective drug therapy exists. Based upon strong preliminary evidence by this research team that a group of proteins (FGFs and FGFRs) involved in embryonic development, wound healing and other critical cellular pathways likely serve as key drivers in the onset of androgen pathway-independent PCa, Nelson and colleagues will do the necessary preclinical work to bring FGF/FGFR inhibitors to clinical trials. They will also study human tissue samples derived from men who have expired from metastatic PCa to determine what other genes and proteins may be at play in the development of androgen pathway-independent PCa. This work will lead to novel drug targets against APIPC.
2013-2015 Movember-PCF Challenge Award ($1 Million)
Project Title: MYC RNAi Nanoparticles for Metastatic Prostate Cancer Treatment
Principal Investigator: Omid Farokhzad, MD (Harvard Medical School)
Co-investigators: Angelo De Marzo, MD, PhD (Johns Hopkins), Charles Bieberich, PhD (University of Maryland), Srinivasan Yegnasubramanian, MD, PhD (Johns Hopkins), Jinjun Shi, PhD (Harvard Medical School)
Description: The MYC gene and its protein are commonly overexpressed in prostate cancer, both in the early stages of the disease, as well as during its progression and metastatic spread. The MYC gene is often aberrantly activated in many cancers and has been implicated in prostate cancer progression to therapy resistance. Therefore MYC is an excellent therapeutic target. However, MYC has traditionally been considered “undruggable” and no effective inhibitors have been identified against this driver of prostate cancer. Dr. Omid Farokhzad and his team will employ a unique nanoparticle strategy to target MYC and inhibit its downstream signaling activity on other genes. Dr. Farokhzad and colleagues have previously successfully developed targeted nanoparticle technologies and brought these from conception to human clinical trials.
To target MYC in prostate cancer, the team will develop innovative self-assembling nanoparticles for the treatment of metastatic prostate cancer. These self-assembling nanoparticles will be designed to carry an internal payload of siRNAs, or small interfering RNAs that silence the expression and activity of specific target genes. SiRNAs are short chains of nucleic acids that can be used to block the production in our bodies of proteins that cause cancer to grow. But if siRNAs are injected directly into a patient’s bloodstream, enzymes will quickly chew up and destroy this free-floating siRNA. The researchers’ nanoparticle delivery mechanism cleverly hides away siRNA in nanoparticles so the nucleic acid chains can make it safely to cancer cells, where they can go to work to eradicate the tumor.
To guide their siRNA-carrying nanoparticles directly to prostate cancer cells, the nanoparticles will be decorated on their surface with targeting agents that will specifically deliver them to prostate tumors, avoiding normal tissue. This will lessen side effects as only cancer cells or the tumor microenvironment will be affected.
Dr. Farokhzad and colleagues will evaluate the efficacy of these nanoparticles to eradicate early invasive carcinoma, advanced localized cancer, and metastatic disease in a first-in-field, genetically engineered mouse model of metastatic disease that expresses MYC. The successful completion of this project will generate a nanoparticle candidate ready for preclinical and clinical development.
What this means for patients: Dr. Farokhzad and his team will use this Challenge Award to develop a novel nano-therapeutic that delivers bits of nucleic acid called siRNAs directly to prostate cancer cells in order to eradicate those cancer cells. Their novel therapeutic will use advanced nanotechnology to target a cancer-associated gene, MYC, that has long-been considered “undruggable.” Additionally, because their unique nanoparticles will home directly to the prostate tumors, healthy tissue will remain largely unaffected and side effects will be limited.
2013-2015 Movember-PCF Challenge Award ($1 Million)
Project Title: Immunotherapy for Prostate Cancer Combining Targeted Inhibition of STAT3-mediated Immunosuppression with CAR-engineered T-cells
Principal Investigator: Stephen J. Forman, MD (City of Hope)
Co-investigators: Christine E. Brown, PhD (City of Hope), Marcin Kortylewski, PhD (City of Hope), Saul J. Priceman, PhD (City of Hope), Sumanta Pal, MD (City of Hope), Joycelynne Palmer, PhD (City of Hope)
Description: Dr. Forman and his team will create a novel combination therapy that will empower a prostate cancer patient’s immune system to eliminate his cancer. T-cells are a specialized type of immune cell with extraordinary surveillance and cell-killing capabilities. Dr. Forman’s group will engineer a patient’s own T-cells to recognize and kill prostate cancer cells. This T-cell therapy, termed “chimeric antigen receptor (CAR) T-cells,” is a form of “live” therapy similar in principle to vaccination, in that once administered, T-cells can persist long term and provide ongoing tumor cell surveillance and protection from recurrence. To enhance the efficacy of these engineered T-cells, Dr. Forman’s group will deliver a second agent, “CpG-STAT3 siRNA,” that suppresses an immune-inhibiting and oncogenic protein, thereby simultaneously promoting T-cell activity while impeding tumor cell growth and survival mechanisms. This therapy will be tested in pre-clinical studies to benchmark efficacy and will ultimately be advanced into human clinical investigations. If successful, this project will lead to the development of a powerful immunotherapeutic treatment modality for prostate cancer patients.
What this means for patients:
Although the immune system is the body’s potent natural defense against dangers, including invading bacteria and viruses, and internal upsets such as cancer cells, it has been historically and frustratingly difficult to create therapies that alter our immune system in a way that significantly slows prostate cancer growth. This is because successful tumors create an environment that inhibits the ability of the immune system to recognize and kill tumor cells. Dr. Forman’s team is developing a novel combination therapy approach that will, A) engineer a prostate cancer patient’s own immune system to recognize and kill cancer cells, and B) use RNA interference to limit the amount of a protein (STAT3) that is both an oncogene and blocks the immune system from becoming highly activated. These agents are expected to act together in synergy in altering a patient’s immune system while suppressing cancer cell growth in order to deliver a triple-knockout punch to prostate cancer cells. The researchers will do the necessary preclinical research on this combination therapy, and hope to bring these agents to clinical trials as early as 2016.
2013-2015 PCF- A. David Mazzone Challenge Award ($500,000)
Project Title: Synergistic immune and lipid metabolism targeting for metastatic prostate cancer therapy.
Principal Investigator: Jennifer Wu, PhD (Medical University of South Carolina)
Co-investigators: James Norris, PhD (MUSC), Michael Lilly, MD (MUSC), Xiang Liu, PhD (MUSC), Ali Goshayan, MD (MUSC)
Description: Dr. Jennifer Wu and colleagues propose to evaluate a combinatorial strategy that recruits a prostate cancer patient’s immune system to eliminate castration resistant prostate cancer. The team has developed a novel antibody that suppresses growth of prostate tumors and prevents the progression to metastasis. This antibody, BSG510 targets the protein sMIC expressed by prostate tumors, and activates the immune system to specifically induce cell death in tumors.
Dr. Wu and her team have also developed a unique small molecule inhibitor, LCL521 that sensitizes tumors to attack by the immune system. Under the PCF- A. David Mazzone Challenge Award, Dr. Wu and her colleagues propose to therapeutically combine the immune stimulatory antibody and the small molecule inhibitor for 1) maximal activation of the immune system primed to kill cancer cells and 2) maximal sensitization of prostate tumors to immune cell killing. They will test the combination in ‘humanized’ prostate cancer mouse models that immunologically and pathologically recapitulate human disease. The researchers will evaluate whether the antibody+inhibitor combination can potentially synergize to eradicate primary and metastatic prostate cancer. They will also evaluate if this combination can potentially delay or prevent the progression of the disease to castration-resistance.
What this means for patients: Dr. Wu and her team are evaluating a combination of two therapies for the treatment of prostate cancer.